Lpa receptor antagonists and uses thereof

ABSTRACT

The present disclosure relates generally to compounds that bind to Lysophosphatidic Acid Receptor 1 (LPAR1) and act as antagonists of LPAR1. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of LPAR1, including fibrosis and liver diseases such as non alcoholic steatohepatitis (NASH).

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.provisional application No. 63/034,190, filed on Jun. 3, 2020, which ishereby incorporated herein by reference in its entirety for allpurposes.

FIELD

The present disclosure relates to compounds that bind to and act asantagonists of a lysophosphatidic acid (LPA) receptor, such as LPAR1.The disclosure further relates to the use of the compounds for thetreatment and/or prophylaxis of diseases and/or conditions associatedwith one or more LPA receptors, e.g., an LPAR1 associated disease orcondition.

BACKGROUND

Lysophosphatidic acids (mono-acyl-glycerol-3-phosphate, LPA) are a classof biologically active phospholipids that can be produced fromlysophosphatidyl choline (LPC), e.g., by the enzyme autotaxin. A typicalLPA has a glycerol, an ester-linked fatty acid at the sn-1 position, anda phosphate head group at the sn-3 position. LPA with various fattyacids have been identified, including palmitoyl LPA (16:0), stearoyl LPA(18:0), oleoyl LPA (18:1), linoleoyl LPA (18:2) and arachidonyl LPA(20:4). LPA exerts a wide range of cellular responses, such asproliferation, differentiation, survival; migration, adhesion, invasion,and morphogenesis through a family of rhodopsin-like G protein-coupledreceptors (GPCRs). Six LPA receptors have been been characterized andwere found to differ in their tissue distribution and downstreamsignaling pathways. These six LPA receptors are often referred tointerchangeably as LPAR1-6 (gene) or LPA1-6 (protein). LPA receptormediated signaling has been shown to influence many biological processessuch as wound healing, immunity, carcinogenesis, angiogenesis andneurogenesis.

In vivo studies involving LPA receptor-deficient mice or certain toolcompounds have suggested a potential of LPA receptors as possible drugtargets in a variety of diseases including cancer, fibrosis,inflammation, pain, and cardiovascular diseases. More recently, LPAR1antagonists have been studied clinically in connection with fibroticdisase states such as idiopathic pulmonary fibrosis (IPF) and systemicsclerosis.

A need remains for LPA antagonists with desirable selectivity, potency,metabolic stability, or reduced detrimental effects.

SUMMARY

The present disclosure provides compounds useful as inhibitors ofLysophosphatidic Acid Receptor 1 (LPAR1). The disclosure further relatesto the use of the compounds for the treatment and/or prophylaxis ofdiseases and/or conditions through binding of LPAR1 by said compounds.

In one embodiment, provided herein is a compound of Formula (I),

or a pharmaceutically acceptable salt thereof,wherein:

-   R¹ is hydrogen or C₁₋₆ alkyl optionally substituted with 1 to 3    substituents, which can be the same or different, each independently    selected from halogen, cyano, C₁₋₄ alkoxy, and C₃₋₁₀ cycloalkyl; or-   R¹ is C₃₋₆ cycloalkyl optionally substituted with 1 to 3    substituents, which can be the same or different, each independently    selected from halogen, cyano, C₁₋₄ alkoxy, and C₁₋₆ alkyl;-   each R², which can be the same or different, is independently    selected from hydrogen, halogen, cyano, oxo, C₁₋₄ alkyl, C₃₋₁₀    cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, 6 to 10    membered aryl, 5 to 10 membered heteroaryl having 1 to 4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur,    —N(R^(2A1))(R^(2A2)), —O—R^(2A1), —S—R^(2A1),    —C(O)N(R^(2A1))(R^(2A2)), —NR^(2A1)C(O)R^(2A2),    —NR^(2A1)C(O)N(R^(2A2))(R^(2A3)), —S(O)₀₋₂R^(2A1),    —S(O)₂N(R^(2A1))(R^(2A2)), and —NR^(2A1)S(O)₂R^(2A2), wherein each    R^(2A1), R^(2A2), and R^(2A3) is independently hydrogen or C₁₋₆    alkyl, wherein each R² alkyl, cycloalkyl, heterocyclic, aryl, and    heteroaryl is optionally substituted with 1 to 4 R^(2B), which can    be the same or different, wherein each R^(2B) is independently C₁₋₄    alkyl, C₁₋₄ alkoxy, hydroxy, halogen, or cyano;-   each R³, which can be the same or different, is independently    selected from deuterium, halogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, or    C₁₋₄ alkoxy, wherein each C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl, is    optionally substituted with 1 to 3 halogens;-   R⁴ is C₁₋₆ alkyl optionally substituted with 1 to 3 substituents,    which can be the same or different, each independently selected from    halogen, cyano, C₁₋₄ alkoxy, —C(O)N(R^(4A1)) and    —N(R^(4A1))(R^(4A2)), wherein each R^(4A1) and R^(4A2) is    independently H, C₁₋₆ alkyl, or C₃₋₁₀ cycloalkyl; or-   R⁴ is C₃₋₆ cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, wherein the cycloalkyl or heterocyclyl are optionally    substituted with 1 to 3 substituents, which can be the same or    different, each independently selected from halogen, cyano, C₁₋₄    alkyl and C₁₋₄ alkoxy;-   m is 0, 1, 2, 3, or 4;-   n is 0, 1, 2, or 3;-   is 0, 1, 2, or 3;-   each of X¹, X², and X³ is independently selected from CH and N;-   each U is independently —CH═, —CH₂—, —N═, —NH—, or —O—;-   each Y¹ and Y² is independently hydrogen, deuterium, or C₁₋₆ alkyl    optionally substituted with 1 to 3 substituents, which can be the    same or different, each independently selected from deuterium,    halogen, cyano, C₂₋₃ alkynyl, C₁₋₄ alkoxy, and —C(O)NH—(C₁₋₄H₃₋₉);    and-   Z is C₁₋₈ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₂ aryl, 3 to 12    membered heterocyclyl having 1 to 4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered    heteroaryl having 1 to 4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl,    aryl, heterocyclyl, or heteroaryl are each optionally substituted    with 1 to 3 substituents, which can be the same or different, each    independently selected from halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    and C₃₋₆ cycloalkyl, wherein the C₁₋₄ alkyl is optionally    substituted with 1 to 3 substituents, which can be the same or    different, each selected from C₁₋₄ alkoxy and halogen; or-   Y¹ and Z together with the carbon to which they are attached form    C₃₋₆ cycloalkyl, C₆₋₁₂ aryl, 3 to 12 membered heterocyclyl having 1    to 4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, wherein    the cycloalkyl, aryl, heterocyclyl, or heteroaryl are each    optionally substituted with 1 to 3 substituents, which can be the    same or different, each independently selected from cyano, C₁₋₄    alkyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl and halogen, wherein the C₁₋₄ alkyl    is optionally substituted with 1 to 3 substituents, which can be the    same or different, each independently selected from C₁₋₄ alkoxy and    halogen, and wherein the C₆₋₁₀ aryl is optionally substituted with 1    to 3 substituents, which can be the same or different, each    independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, and halogen,    and Y² is hydrogen or deuterium.

In some embodiments, provided herein are pharmaceutical compositionscomprising a compound provided herein, or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient or carrier. Insome embodiments, the pharmaceutical compositions comprise atherapeutically effective amount of a compound provided herein, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, orpharmaceutically acceptable salts thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, orpharmaceutically acceptable salts thereof.

In some embodiments, the present disclosure provides methods ofinhibiting LPAR1 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (e.g., a compound of Formula (I), (Ia), (II),(IIa), (IIIa)-(IIIg), (VIa)-(Vj)), or pharmaceutically acceptable saltthereof, or a pharmaceutical composition provided herein.

In some embodiments, the present disclosure provides methods of treatinga patient having an LPAR1 mediated condition, comprising administeringto the patient a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), (VIa)-(Vj)), or pharmaceutically acceptable salt thereof,or a pharmaceutical composition provided herein.

DETAILED DESCRIPTION

The present disclosure relates to LPA receptor antagonists, such asantagonists of LPAR1. The disclosure also relates to compositions andmethods relating to LPAR1 antagonists and the use of such compounds fortreatment and/or prophylaxis of LPAR1-mediated diseases and conditions.The disclosure also relates to compositions and methods of treatingand/or preventing liver disease including an LPAR1 antagonist incombination with one or more additional therapeutic agents.

It is commonly believed that patients with certain LPAR1-mediateddiseases, such as cancer, fibrosis, inflammation, pain, andcardiovascular diseases, or liver diseases including non alcoholic fattyliver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) canbenefit from the treatment with an LPAR1 antagonist and optionally oneor more additional therapeutic agents.

Definitions and General Parameters

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

As used in the present specification, the following terms and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named. A solid line comingout of the center of a ring indicates that the point of attachment for asubstituent on the ring can be at any ring atom. For example, R^(a) inthe below structure can be attached to any of the five carbon ring atomsor R^(a) can replace the hydrogen attached to the nitrogen ring atom:

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings,wherein x and y are numerical ranges, such as “3 to 12-memberedheterocyclyl”, refers to a ring containing x-y atoms (e.g., 3-12), ofwhich up to 80% may be heteroatoms, such as N, O, S, P, and theremaining atoms are carbon.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, or alkylyl group, an “arylene” group oran “arylenyl” group, or arylyl group, respectively.

“A compound disclosed herein” or “a compound of the present disclosure”or “a compound provided herein” or “a compound described herein” refersto the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg),(VIa)-(Vj). Also included are the specific Compounds 1 to 32 providedherein (e.g., Examples 1-33).

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl), or 1 to 3 carbon atoms(i.e., C₁₋₃ alkyl). Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. When an alkyl residue having a specific number ofcarbons is named by chemical name or identified by molecular formula,all positional isomers having that number of carbons may be encompassed;thus, for example, “butyl” includes n-butyl (i.e. —(CH₂)₃CH₃), sec-butyl(i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e. —CH₂CH(CH₃)₂) and tert-butyl (i.e.—C(CH₃)₃); and “propyl” includes n-propyl (i.e. —(CH₂)₂CH₃) andisopropyl (i.e. —CH(CH₃)₂).

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of whichmay be optionally substituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Fused” refers to a ring which is bound to an adjacent ring. In someembodiments the fused ring system is a heterocyclyl. In some embodimentsthe fused ring system is a oxabicyclohexanyl. In some embodiments thefused ring system is

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as alkylenyl group, analkylenyl group containing one or two heteroatoms, or a singleheteroatom. Quinuclidinyl and admantanyl are examples of bridged ringsystems. In some embodiments the bridged ring is a bicyclopentanyl(bicycle[1.1.1]pentanyl) or bicyclooctanyl (bicycle[2.2.2]octanyl). Insome embodiments, the bridge ring is

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents. In some embodiments the spirosubstituent is a spiropentanyl (spiro[a.b]pentanyl), spirohexanyl,spiroheptanyl, or spirodecanyl. In some embodiments the spirosubstituent is

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 carbon ring atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 ringheteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen, and sulfur. Examples of heteroaryl groups includepyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to anon-aromatic cyclic alkyl group, with one or more ring heteroatomsindependently selected from nitrogen, oxygen and sulfur. As used herein,“heterocyclyl” or “heterocyclic ring” or “heterocycle” refer to ringsthat are saturated or partially saturated unless otherwise indicated,e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to rings that are partially saturated wherespecified. The term “heterocyclyl” or “heterocyclic ring” or“heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclylgroup having at least one double bond). A heterocyclyl may be a singlering or multiple rings wherein the multiple rings may be fused, bridged,or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 carbon ring atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 carbon ring atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 carbon ring atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 carbon ringatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 carbon ring atoms (i.e., C₃₋₈heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,dioxolanyl, azetidinyl, and morpholinyl. As used herein, the terms“heterocycle”, “heterocyclyl”, and “heterocyclic ring” are usedinterchangeably.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R^(c), where R^(c) is alkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl aremethylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH₂ group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” means that any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, amino,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one ormore substituents including alkyl, amino, haloalkyl, heterocyclyl,cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or moresubstituents including halo, alkyl, amino, haloalkyl, cycloalkyl,heterocyclyl, heteroaryl, alkoxy, and cyano; “substituted heteroaryl”refers to an heteroaryl group having one or more substituents includinghalo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to agroup —S(O)₂R, in which R is substituted with one or more substituentsincluding alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Inother embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is unsubstituted.

In some embodiments, a substituted cycloalkyl, a substitutedheterocyclyl, a substituted aryl, and/or a substituted heteroarylincludes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl thathas a substituent on the ring atom to which the cycloalkyl,heterocyclyl, aryl, and/or heteroaryl is attached to the rest of thecompound. For example, in the below moiety, the cyclopropyl issubstituted with a methyl group:

The disclosures illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising”, “including,” “containing”, etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the disclosure claimed.

The compounds of the present disclosure can be in the form of apharmaceutically acceptable salt. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases or acids, including inorganic bases or acids and organicbases or acids. The compounds of the present disclosure can be in theform of a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids, including inorganic bases or acidsand organic bases or acids. In case the compounds of the presentdisclosure contain one or more acidic or basic groups, the disclosurealso comprises their corresponding pharmaceutically or toxicologicallyacceptable salts, in particular their pharmaceutically utilizable salts.Thus, the compounds of the present disclosure which contain acidicgroups can be present on these groups and can be used according to thedisclosure, for example, as alkali metal salts, alkaline earth metalsalts or ammonium salts. More precise examples of such salts includesodium salts, potassium salts, calcium salts, magnesium salts or saltswith ammonia or organic amines such as, for example, ethylamine,ethanolamine, triethanolamine, amino acids, or other bases known topersons skilled in the art. The compounds of the present disclosurewhich contain one or more basic groups, i.e. groups which can beprotonated, can be present and can be used according to the disclosurein the form of their addition salts with inorganic or organic acids.Examples of suitable acids include hydrogen chloride, hydrogen bromide,phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known topersons skilled in the art.

If the compounds of the present disclosure simultaneously contain acidicand basic groups in the molecule, the disclosure also includes, inaddition to the salt forms mentioned, inner salts or betaines(zwitterions). The respective salts can be obtained by customary methodswhich are known to the person skilled in the art like, for example, bycontacting these with an organic or inorganic acid or base in a solventor dispersant, or by anion exchange or cation exchange with other salts.

The present disclosure also includes all salts of the compounds of thepresent disclosure which, owing to low physiological compatibility, arenot directly suitable for use in pharmaceuticals but which can be used,for example, as intermediates for chemical reactions or for thepreparation of pharmaceutically acceptable salts. Acids and bases usefulfor reaction with an underlying compound to form pharmaceuticallyacceptable salts (acid addition or base addition salts respectively) areknown to one of skill in the art. Similarly, methods of preparingpharmaceutically acceptable salts from an underlying compound (upondisclosure) are known to one of skill in the art and are disclosed infor example, Berge, at al. Journal of Pharmaceutical Science, January1977 vol. 66, No. 1, and other sources.

Furthermore, compounds disclosed herein may be subject to tautomerism.Where tautomerism, e.g., keto-enol tautomerism, of compounds or theirprodrugs may occur, the individual forms, like, e.g., the keto and enolform, are each within the scope of the disclosure as well as theirmixtures in any ratio. The same applies for stereoisomers, like, e.g.,enantiomers, cis/trans isomers, diastereomers, conformers, and the like.

The term “protecting group” refers to a moiety of a compound that masksor alters the properties of a functional group or the properties of thecompound as a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. The term “deprotecting” refers toremoving the protecting group.

It will be appreciated by the skilled person that when lists ofalternative substituents include members which, because of their valencyrequirements or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read with the knowledge of the skilledperson to include only those members of the list which are suitable forsubstituting the particular group.

Further the compounds of the present disclosure may be present in theform of solvates, such as those which include as solvate water, orpharmaceutically acceptable solvates, such as alcohols, in particularethanol. A “solvate” is formed by the interaction of a solvent and acompound.

In certain embodiments, provided are optical isomers, racemates, orother mixtures thereof of the compounds described herein or apharmaceutically acceptable salt or a mixture thereof. If desired,isomers can be separated by methods well known in the art, e.g. byliquid chromatography. In those situations, the single enantiomer ordiastereomer, i.e., optically active form, can be obtained by asymmetricsynthesis or by resolution. Resolution can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using for example, a chiralhigh-pressure liquid chromatography (HPLC) column.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers,”which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another. “Diastereomers” are stereoisomers thathave at least two asymmetric atoms, but which are not mirror-images ofeach other.

Compounds disclosed herein and their pharmaceutically acceptable saltsmay, in some embodiments, include an asymmetric center and may thus giverise to enantiomers, diastereomers, and other stereoisomeric forms thatmay be defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)- for amino acids. Some embodiments include all suchpossible isomers, as well as their racemic and optically pure forms.Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)- isomersmay be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh-pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers.

Compositions provided herein that include a compound described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof mayinclude racemic mixtures, or mixtures containing an enantiomeric excessof one enantiomer or single diastereomers or diastereomeric mixtures.All such isomeric forms of these compounds are expressly included hereinthe same as if each and every isomeric form were specifically andindividually listed.

Any formula or structure given herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphoros, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients. Isotopically labeledcompounds of this disclosure and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

The disclosure also includes “deuterated analogs” of compounds disclosedherein, in which from 1 to n hydrogens attached to a carbon atom is/arereplaced by deuterium, in which n is the number of hydrogens in themolecule. Such compounds may exhibit increased resistance to metabolismand thus be useful for increasing the half-life of any compound ofFormula (I) when administered to a mammal, e.g., a human. See, e.g.,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have beneficial DMPK (drug metabolism andpharmacokinetics) properties, relating to distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life, reduceddosage requirements and/or an improvement in therapeutic index. An ¹⁸Flabeled compound may be useful for PET or SPECT studies.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Furthermore, the present disclosure provides pharmaceutical compositionscomprising a compound of the present disclosure, or a prodrug compoundthereof, or a pharmaceutically acceptable salt or solvate thereof asactive ingredient together with a pharmaceutically acceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present disclosurecan encompass any composition made by admixing at least one compound ofthe present disclosure and a pharmaceutically acceptable carrier.

As used herein, “pharmaceutically acceptable carrier” includesexcipients or agents such as solvents, diluents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like that are not deleterious to the disclosedcompound or use thereof. The use of such carriers and agents to preparecompositions of pharmaceutically active substances is well known in theart (see, e.g., Remington's Pharmaceutical Sciences, Mace PublishingCo., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, MarcelDekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

“IC₅₀” or “EC₅₀” refers to the inhibitory concentration required toachieve 50% of the maximum desired effect. In many cases here themaximum desired effect is the inhibition of LPA induced LPAR1activation. This term is obtained using an in vitro assay, such as acalcium mobilization assay, evaluating the concentration-dependentinhibition of LPA induced LPAR1 activity.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival. In someembodiments, the term “treatment” or “treating” means administering acompound or pharmaceutically acceptable salt of Formula (I), (Ia), (II),(IIa), (IIIa)-(IIIg), (VIa)-(Vj) for the purpose of: (i) delaying theonset of a disease, that is, causing the clinical symptoms of thedisease not to develop or delaying the development thereof; (ii)inhibiting the disease, that is, arresting the development of clinicalsymptoms; and/or (iii) relieving the disease, that is, causing theregression of clinical symptoms or the severity thereof.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In some embodiments, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to LPAR1antagonists. The therapeutically effective amount may vary depending onthe subject, and disease or condition being treated, the weight and ageof the subject, the severity of the disease or condition, and the mannerof administering, which can readily be determined by one or ordinaryskill in the art.

List of Abbreviations and Acronyms Abbreviation Meaning ACN or MeCNAcetonitrile aq. Aqueous Bn Benzyl COPD Chronic Obstructive PulmonaryDisease DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide DPPA Diphenylphosphorylazide EA Ethyl acetate EDTA Ethylenediaminetetraacetic acid ESIElectronspray Ionization Et Ethyl Et₂O Diethyl ether EtOAc Ethyl acetateh or hr(s) Hour(s) HBSS Hanks' Balanced Salt solution HCC Hepatocellularcarcinoma HPLC High performance liquid chromatography LCMS or LiquidChromatography Mass Spectrometry LC/MS LPA Lysophosphatidic acid LPCLysophosphatidylcholine Me Methyl MeOH Methanol MS Mass Spectrometry m/zMass-to-charge ratio NADPH Dihydronicotinamide-adenine dinucleotidephosphate NAFLD Non-alcoholic fattyl liver disease NASH Non-alcoholicsteatohepatitis NMR Nuclear Magnetic Resonance spectroscopy PBC PrimaryBiliary Cirrhosis PE Petroleum ether PSC Primary Sclerosing Choleangitisrpm Revolutions per minute RT or rt Room temperature sat. SaturatedTEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl TFA Trifluoroacetic acid THFTetrahydrofuran T3P Propanephosphonic acid anhydride

As used herein, an “LPAR1 antagonist” refers to any agent that iscapable of binding and inhibiting LPAR1. LPAR1, also known as LPA1, is aGPCR that binds the lipid signaling molecule lysophosphatidic acid(LPA). Exemplary reference sequences for LPAR1 include the NCBIReference Sequences NP_001392 (human protein), NP_001277415 (mouseprotein), NM_001401 (human mRNA), and NM_001290486 (mouse mRNA). LPAR1antagonists can act as competitive inhibitors of full or partial LPAR1agonists, or as inverse agonists. The activity of an LPAR antagonist maybe measured by methods known in the art, such as those described andcited in Castelino et al., 2010 Arthritis Rheum. 2011 May; 63(5):1405-1415 or Swaney et al., J Pharmacol Exp Ther. 2011 March;336(3):693-700.

As used herein, an “ACC inhibitor” refers to any agent that is capableof binding and inhibiting Acetyl-CoA carboxylase (ACC). ACC inhibitorscan act as inhibitors or partial inhibitors of ACC. The agent can be achemical compound or biological molecule (e.g., a protein or antibody).The activity of an ACC inhibitor can be measured by methods known in theart, such as those described and cited in U.S. Pat. No. 8,969,557 and/orin U.S. Pat. No. 10,208,063, both of which are incorporated herein byreference in their entirety.

As referred to herein, an “ASK1 inhibitor” can be any agent that iscapable of inactivating an apoptosis signal regulating kinase 1 (ASK1)protein. The agent can be a chemical compound or biological molecule(e.g., a protein or antibody). The ASK1 protein activity can be measuredby several different methods. For example, the activity of an ASK1protein can be determined based on the ability of the ASK1 protein tophosphorylate a substrate protein. Methods for identifying an ASK1inbibitor are known (see, e.g., U.S. 2007/0276050). Exemplary ASK1substrate proteins include MAPKK3, MAPKK4, MAPKK6, MAPKK7, or fragmentsthereof. The ASK1 protein activity can also be measured by thephosphorylation level of the ASK1 protein, for example, thephosphorylation level of a threonine residue in the ASK1 proteincorresponding to threonine 838 (T838) of a human full-length ASK1protein or threonine 845 (T845) of a mouse full-length ASK1 protein. Forexample, where the ASK1 protein comprises a full-length human ASK1protein sequence, an ASK1 inhibitor may attenuate phosphorylation ofT838 in the full-length human ASK1 protein sequence. A site-specificantibody against human ASK1 T838 or mouse ASK1 T845 may be used todetect the phosphohorylation level.

As used herein, a “FXR agonist” refers to any agent that is capable ofbinding and activating farnesoid X receptor (FXR) which can be referredto as bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1,group H, member 4) receptor. FXR agonists can act as agonists or partialagonists of FXR. The agent can be a chemical compound or biologicalmolecule (e.g., a protein or antibody). The activity of an FXR agonistcan be measured by several different methods, e.g., in an in vitro assayusing the fluorescence resonance energy transfer (FRET) cell free assayas described in Pellicciari, et al. Journal of Medicinal Chemistry, 2002vol. 15, No. 45:3569-72.

Compounds

In one embodiment, provided herein is a compound of Formula (I),

or a pharmaceutically acceptable salt thereof,wherein:

-   R¹ is hydrogen or C₁₋₆ alkyl optionally substituted with 1 to 3    substituents, which can be the same or different, each independently    selected from halogen, cyano, C₁₋₄ alkoxy, and C₃₋₁₀ cycloalkyl; or-   R¹ is C₃₋₆ cycloalkyl optionally substituted with 1 to 3    substituents, which can be the same or different, each independently    selected from halogen, cyano, C₁₋₄ alkoxy, and C₁₋₆ alkyl;-   each R², which can be the same or different, is independently    selected from hydrogen, halogen, cyano, oxo, C₁₋₄ alkyl, C₃₋₁₀    cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, 6 to 10    membered aryl, 5 to 10 membered heteroaryl having 1 to 4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur,    —N(R^(2A1))(R^(2A2)), —O—R^(2A1), —S—R^(2A1)C(O)N(R^(2A1))(R^(2A2)),    —NR^(2A1)C(O)R^(2A2), —NR^(2A1)C(O)N(R^(2A2))(R^(2A3)),    —S(O)₀₋₂R^(2A1), —S(O)₂N(R^(2A1))(R^(2A2)), and    —NR^(2A1)S(O)₂R^(2A2), wherein each R^(2A1), R^(2A2), and R^(2A3) is    independently hydrogen or C₁₋₆ alkyl, wherein each R² alkyl,    cycloalkyl, heterocyclic, aryl, and heteroaryl is optionally    substituted with 1 to 4 R^(2B), which can be the same or different,    wherein each R^(2B) is independently C₁₋₄ alkyl, C₁₋₄ alkoxy,    hydroxy, halogen, or cyano;-   each R³, which can be the same or different, is independently    selected from deuterium, halogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, or    C₁₋₄ alkoxy, wherein each C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl, is    optionally substituted with 1 to 3 halogens;-   R⁴ is C₁₋₆ alkyl optionally substituted with 1 to 3 substituents,    which can be the same or different, each independently selected from    halogen, cyano, C₁₋₄ alkoxy, —C(O)N(R^(4A1)) and    —N(R^(4A1))(R^(4A2)) wherein each R^(4A1) and R^(4A2) is    independently H, C₁₋₆ alkyl, or C₃₋₁₀ cycloalkyl; or-   R⁴ is C₃₋₆ cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, wherein the cycloalkyl or heterocyclyl are optionally    substituted with 1 to 3 substituents, which can be the same or    different, each independently selected from halogen, cyano, C₁₋₄    alkyl and C₁₋₄ alkoxy;-   m is 0, 1, 2, 3, or 4;-   n is 0, 1, 2, or 3;-   is 0, 1, 2, or 3;-   each of X¹, X², and X³ is independently selected from CH and N;-   each U is independently —CH═, —CH₂—, —N═, —NH—, or —O—;-   each Y¹ and Y² is independently hydrogen, deuterium, or C₁₋₆ alkyl    optionally substituted with 1 to 3 substituents, which can be the    same or different, each independently selected from deuterium,    halogen, cyano, C₂₋₃ alkynyl, C₁₋₄ alkoxy, and —C(O)NH—(C₁₋₄H₃₋₉);    and-   Z is C₁₋₈ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₂ aryl, 3 to 12    membered heterocyclyl having 1 to 4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered    heteroaryl having 1 to 4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl,    aryl, heterocyclyl, or heteroaryl are each optionally substituted    with 1 to 3 substituents, which can be the same or different, each    independently selected from halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    and C₃₋₆ cycloalkyl, wherein the C₁₋₄ alkyl is optionally    substituted with 1 to 3 substituents, which can be the same or    different, each selected from C₁₋₄ alkoxy and halogen; or-   Y¹ and Z together with the carbon to which they are attached form    C₃₋₆ cycloalkyl, C₆₋₁₂ aryl, 3 to 12 membered heterocyclyl having 1    to 4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, wherein    the cycloalkyl, aryl, heterocyclyl, or heteroaryl are each    optionally substituted with 1 to 3 substituents, which can be the    same or different, each independently selected from cyano, C₁₋₄    alkyl, C₁₋₄ alkoxy, C₆₋₁₀ aryl and halogen, wherein the C₁₋₄ alkyl    is optionally substituted with 1 to 3 substituents, which can be the    same or different, each independently selected from C₁₋₄ alkoxy and    halogen, and wherein the C₆₋₁₀ aryl is optionally substituted with 1    to 3 substituents, which can be the same or different, each    independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, and halogen,    and Y² is hydrogen or deuterium.

In some embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, is a compound of Formula (Ia) orpharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula (I) or (Ia), R¹ ishydrogen.

In some embodiments of the compound of Formula (I) or (Ia), R⁴ is C₁₋₃alkyl optionally substituted with 1 to 3 substituents, which can be thesame or different, independently selected from —CN and —F. In someembodiments of the compound of Formula (I) or (Ia), R⁴ is —CH₃.

In some embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, is a compound of Formula (II):

or pharmaceutically acceptable salt thereof;wherein:

-   R¹ is hydrogen;-   each R² is independently selected from deuterium, cyano, hydroxy,    halogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, or C₁₋₄ alkoxy, wherein the    C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl, is optionally substituted with 1 to    3 halogens;-   W¹ is —CH₂—;-   W² is —CH═, —CH₂—, or —O—;-   W³ is —CH═, —CH₂—, —O—, or —NH—; and-   p and q are each independently 0 or 1.

In some embodiments, the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt thereof, is a compound of Formula(IIa):

In some embodiments of the compound of Formula (I), (Ia), (II), or(IIa), p is 0 and q is 0. In some embodiments of the compound of Formula(I), (Ia), (II), or (IIa), p is 0 and q is 1. In some embodiments of thecompound of Formula (I), (Ia), (II), or (IIa), p is 1 and q is 1.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIIa):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIIb):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1, 2, 3, or 4; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIIc):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1 or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIId):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIIe):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIIf):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1, 2, or 3; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IIIg):

or pharmaceutically acceptable salt thereof;wherein:m is 0, 1, 2, 3, or 4; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVa):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVb):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, 2, 3, or 4; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVc):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVd):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVe):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, or 2.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVf):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVg):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, or 2.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVh):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2; ando is 0, 1, or 2.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVi):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, or 2;o is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (I), (Ia), (II), or (IIa),or pharmaceutically acceptable salt thereof, is a compound of Formula(IVj):

or pharmaceutically acceptable salt thereof;whereinm is 0, 1, 2, 3, or 4; ando is 0, 1, 2, or 3.

In some embodiments of the compound of Formula (IIIa)-(IIIg) or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, m is 0, 1, or2. In some embodiments of the compound of Formula (IIIa)-(IIIg) or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, o is 0 or 1.In some embodiments of the compound of Formula (IIIa)-(IIIg) or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, m is 0 and ois 0. In some embodiments of the compound of Formula (IIIa)-(IIIg) or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, m is 1 and ois 0. In some embodiments of the compound of Formula (IIIa)-(IIIg) or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, m is 2 and ois 0. In some embodiments of the compound of Formula (IIIa)-(IIIg) or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, m is 0 and ois 1.

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, each R², which can be the same or different, is independentlyselected from hydrogen, halogen, cyano, oxo, C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, 6 to 10membered aryl, 5 to 10 membered heteroaryl having 1 to 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur,—N(R^(2A1))(R^(2A2)), —O—R^(2A1), —S—R^(2A1), —C(O)N(R^(2A1))(R^(2A2)),—NR^(2A1)C(O)R^(2A2), —NR^(2A1)C(O)N(R^(2A2))(R^(2A3)), —S(O)₀₋₂R^(2A1),—S(O)₂N(R^(2A1))(R^(2A2)), and —NR^(2A1)S(O)₂R^(2A2), wherein eachR^(2A1), R^(2A2), and R^(2A3) is independently hydrogen or C₁₋₆ alkyl,wherein each R² alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl isoptionally substituted with 1 to 4 R^(2B), which can be the same ordifferent, wherein each R^(2B) is independently C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, halogen, or cyano. In some embodiments of the compound ofFormula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), orpharmaceutically acceptable salt thereof, each R², which can be the sameor different, is independently C₁₋₄ alkyl, 6 to 10 membered aryl, C₁₋₄alkoxy, or halogen, wherein each C₁₋₄ alkyl is optionally substitutedwith 1 to 4 halogen. In some embodiments of the compound of Formula (I),(Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceuticallyacceptable salt thereof, each R², which can be the same or different, isindependently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, and halogen. Insome embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, each R², which can be the same or different, is independently—CH₃, —CF₃, —C₂H5, phenyl, or —F. In some embodiments of the compound ofFormula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), orpharmaceutically acceptable salt thereof, each R² is halogen. In someembodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, each R² is —F.

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, each R³, which can be the same or different, is independentlyselected from deuterium, halogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, or C₁₋₄alkoxy, wherein each C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl, is optionallysubstituted with 1 to 3 halogens. In some embodiments of the compound ofFormula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), orpharmaceutically acceptable salt thereof, each R³ is halogen. In someembodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, each R³ is —F.

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Y¹ is hydrogen, deuterium, or C₁₋₆ alkyl optionally substitutedwith 1 to 3 substituents, which can be the same or different, eachindependently selected from deuterium, halogen, cyano, C₂₋₃ alkynyl,C₁₋₄ alkoxy, and —C(O)NH—(C₁₋₄H₃₋₉). In some embodiments of the compoundof Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), orpharmaceutically acceptable salt thereof, Y₁ is C₁₋₄ alkyl optionallysubstituted with 1 to 3 substituents, which can be the same ordifferent, each independently selected from halogen, cyano, and C₁₋₄alkoxy. In some embodiments of the compound of Formula (I), (Ia), (II),(IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Y₁ is methyl optionally substituted with 1 to 3 susbstituents,which can be the same or different, each independently selected from —F,—Cl, —CN, and —O—CH₃. In some embodiments of the compound of Formula(I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), orpharmaceutically acceptable salt thereof, Y₁ is —CH₃ or —CH₂F.

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Z is C₁₋₈ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₂ aryl, 3 to12 membered heterocyclyl having 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or 5 to 12 memberedheteroaryl having 1 to 4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl,aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1to 3 substituents, which can be the same or different, eachindependently selected from halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, andC₃₋₆ cycloalkyl, wherein the C₁₋₄ alkyl is optionally substituted with 1to 3 substituents, which can be the same or different, each selectedfrom C₁₋₄ alkoxy and halogen. In some embodiments of the compound ofFormula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), orpharmaceutically acceptable salt thereof, Z is phenyl, optionallysubstituted with 1 to 3 sustituents, which can be the same or different,each independently selected from halogen and C₁₋₄ alkyl. In someembodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Z is phenyl, optionally substituted with 1 to 3 substituents,which can be the same or different, each independently selected from —Fand —C₁. In some embodiments of the compound of Formula (I), (Ia), (II),(IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Z is

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Z is 5 or 6 membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein theheteroaryl is optionally substituted with 1 to 3 substituents, which canbe the same or different, independently selected from halogen and C₁₋₄alkyl. In some embodiments of the compound of Formula (I), (Ia), (II),(IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, Z is pyridyl, optionally substituted with 1 to 3 substituents,which can be the same or different, each independently selected from —F,—Cl, —Br, and —CH₃. In some embodiments of the compound of Formula (I),(Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceuticallyacceptable salt thereof,

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof Y₁ is —CH₃, and Z is

In some embodiments the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVa)-(IVk), or pharmaceutically acceptable saltthereof Y₁ is —CH₃, and Z is Z is

In some embodiments of the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, is selected from the group consisting of:

or pharmaceutically acceptable salt thereof.

In some embodiments the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, is:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, is:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, is:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or pharmaceutically acceptable saltthereof, is:

or pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions and Modes of Administration

Furthermore, the present disclosure provides pharmaceutical compositionscomprising at least one compound of the present disclosure, or a prodrugcompound thereof, or a pharmaceutically acceptable salt or solvatethereof as active ingredient together with a pharmaceutically acceptablecarrier.

The pharmaceutical composition of the present disclosure mayadditionally comprise one or more other compounds as active ingredientslike a prodrug compound or other enzyme inhibitors.

The compositions are suitable for oral, rectal, topical, parenteral(including subcutaneous, intramuscular, and intravenous), ocular(ophthalmic), pulmonary (nasal or buccal inhalation) or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. They may be conveniently presentedin unit dosage form and prepared by any of the methods well-known in theart of pharmacy.

In practical use, the compounds of the present disclosure can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). In preparing thecompositions for oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like in thecase of oral liquid preparations, such as, for example, suspensions,elixirs and solutions; or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents and the like in the case of oral solidpreparations such as, for example, powders, hard and soft capsules andtablets, with the solid oral preparations being preferred over theliquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or non-aqueous techniques. Such compositions andpreparations should contain at least 0.1 percent of active compound. Thepercentage of active compound in these compositions may, of course, bevaried and may conveniently be between about 2 percent to about 60percent of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be obtained. The active compounds can also be administeredintranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

In some embodiments, the compounds of the present disclosure may also beused as salts with various countercations to yield an orally availableformulation.

The compounds of the present disclosure may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent disclosure. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. In some embodiments,compounds of the present disclosure are administered orally.

Kits

Provided herein are also kits that include a compound of the disclosure,or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixtureof stereoisomers, prodrug, or deuterated analog thereof, and suitablepackaging. In one embodiment, a kit further includes instructions foruse. In one aspect, a kit includes a compound of the disclosure, or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof, and a label and/orinstructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof in a suitable container. The container may be a vial, jar,ampoule, preloaded syringe, and intravenous bag.

Treatment Methods and Uses

The disclosure further relates to the use of compounds disclosed hereinfor the treatment and/or prophylaxis of diseases and/or conditionsthrough binding of LPAR1 by said compounds. Further, the presentdisclosure relates to the use of said compounds for the preparation of amedicament for the treatment and/or prophylaxis of diseases and/orconditions through binding of LPAR1 by said compounds.

Medicaments as referred to herein may be prepared by conventionalprocesses, including the combination of a compound according to thepresent disclosure and a pharmaceutically acceptable carrier.

In some embodiments, provided herein is a method of treating and/orpreventing an LPAR1-mediated disease or condition in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or a pharmaceutically acceptable saltthereof, or a composition comprising a compound of Formula (I), (Ia),(II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj), or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the LPAR1-mediated disease or condition includesthose wherein an absolute or relative excess of LP A is present and/orobserved.

In some embodiments, the LPAR1-mediated disease or condition includesfibrosis, wound healing, cancer, pain, respiratory disorders, allergicdisorders, nervous system disorders, cardiovascular disorders, orinflammatory disorders.

In some embodiments, the LPAR1-mediated disease or condition includesfibrosis. In some embodiments, fibrosis includes pulmonary fibrosis,renal fibrosis, hepatic fibrosis, ocular fibrosis, or cardiac fibrosis.

In some embodiments, the LPAR1-mediated disease or condition includespulmonary fibrosis. In some embodiments, pulmonary fibrosis includesidiopathic pulmonary fibrosis (IPF). In some embodiments pulmonaryfibrosis includes Progressive Fibrotic interstitial lung disease(PF-ILD). In some embodiments, pulmonary fibrosis includes pulmonaryfibrosis secondary to systemic inflammatory disease such as rheumatoidarthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis,radiation induced fibrosis, chronic obstructive pulmonary disease(COPD), scleroderma, chronic asthma, silicosis, asbestos inducedpulmonary or pleural fibrosis, acute lung injury and acute respiratorydistress (including bacterial pneumonia induced, trauma induced, viralpneumonia induced, ventilator induced, non-pulmonary sepsis induced, andaspiration induced).

In some embodiments, the LPAR1-mediated disease or condition includesrenal fibrosis. In some embodiments, renal fibrosis includes chronicnephropathies associated with injury/ibrosis (kidney fibrosis), e.g.,glomerulonephritis secondary to systemic inflammatory diseases such aslupus and scleroderma, diabetes, glomerular nephritis, focal segmentalglomerular sclerosis, IgA nephropathy, hypertension, allograft andAlport; gut fibrosis, e.g., scleroderma, and radiation induced gutfibrosis.

In some embodiments, the LPAR1-mediated disease or condition includesliver fibrosis. In some embodiments, liver fibrosis includes livercirrhosis, alcohol induced liver fibrosis, nonalcoholic steatohepatitis(NASH), biliary duct injury, primary biliary cirrhosis, infection orviral induced liver fibrosis (e.g., chronic HCV infection), andautoimmune hepatitis.

In some embodiments, the LPAR1-mediated disease or condition includeshead and neck fibrosis, e.g., radiation induced.

In some embodiments, the LPAR1-mediated disease or condition includescorneal scarring, e.g., due to LASIK (laser-assisted in situkeratomileusis), corneal transplantation, or trabeculectomy. In someembodiments, a compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or a pharmaceutically acceptable saltthereof, is used to improve the corneal sensitivity decrease caused bycorneal operations such as LASIK or cataract operation, cornealsensitivity decrease caused by corneal degeneration, and dry eye symptomcaused thereby. In some embodiments, a compound of Formula (I), (Ia),(II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj), or a pharmaceuticallyacceptable salt thereof, is used in the treatment or prevention ofocular inflammation and allergic conjunctivitis, vernalkeratoconjunctivitis, and papillary conjunctivitis. In some embodiments,a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj), or a pharmaceutically acceptable salt thereof, is used inthe treatment or prevention of Sjogren disease or inflammatory diseasewith dry eyes.

In some embodiments, the LPAR1-mediated disease or condition includesanother fibrotic condition, such as hypertrophic scarring and keloids,e.g., burn induced or surgical, sarcoidosis, scleroderma, spinal cordinjury/fibrosis, myelofibrosis, vascular restenosis, atherosclerosis,arteriosclerosis, Wegener's granulomatosis, mixed connective tissuedisease, and Peyronie's disease.

In some embodiments, the LPAR1-mediated disease or condition includespain. In some embodiments, pain includes neuropathic pain. In someembodiments, pain includes acute pain. In some embodiments, painincludes chronic pain.

In some embodiments, the LPAR1-mediated disease or condition includescancer. In some embodiments, cancer includes ovarian cancer, coloncancer, prostate cancer, breast cancer, melanoma, head and neck cancer,bowel cancer (colorectal cancer), and thyroid cancer. In someembodiments, cancer includes solid tumors, such as (such as those of thebladder, bowel, brain, breast, endometrium, heart, kidney, lung,lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ(thyroid), prostate, skin (melanoma or basal cell cancer) orhematological tumors (such as the leukemias) at any stage of the diseasewith or without metastases. In some embodiments, cancer includes, acutelymphoblastic leukemia, acute myeloid leukemia, adrenocorticalcarcinoma, anal cancer, appendix cancer, astrocytomas, atypicalteratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladdercancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma),brain stem glioma, brain tumors, brain and spinal cord tumors, breastcancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chroniclymphocytic leukemia, chronic myelogenous leukemia, colon cancer,colorectal cancer, craniopharyngioma, cutaneous T-Cell lymphoma,embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma,esophageal cancer, ewing sarcoma family of tumors, eye cancer,retinoblastoma, gallbladder cancer, gastric (stomach) cancer,gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST),gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cellleukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkinlymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors(endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cellhistiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic leukemia,acute myeloid leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, hair) cell leukemia, liver cancer, non-small celllung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-celllymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrommacroglobulinemia, medulloblastoma, medulloepithelioma, melanoma,mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloidleukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma,non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer,oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma ofbone, ovarian cancer, ovarian epithelial cancer, ovarian germ celltumor, ovarian low malignant potential tumor, pancreatic cancer,papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer,pineal parenchymal tumors of intermediate differentiation, pineoblastomaand supratentorial primitive neuroectodermal tumors, pituitary tumor,plasma cell neoplasm/multiple myeloma, pleuropulmonary blastema, primarycentral nervous system lymphoma, prostate cancer, rectal cancer, renalcell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive, neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor.

In some embodiments, the LPAR1-mediated disease or condition includes arespiratory or allergic disorder. In some embodiments, the respiratoryor allergic disorder includes asthma, peribronchiolar fibrosis,obliterative bronchiolitis, and chronic obstructive pulmonary disease(COPD). In some embodiments, the COPD includes chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation, and cystic fibrosis. In some embodiments, therespiratory disease includes adult respiratory distress syndrome andallergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acutesevere asthma, chronic asthma, clinical asthma, nocturnal asthma,allergen-induced asthma, aspirin-sensitive asthma, exercise-mducedasthma, isocapnic hyperventilation, child-onset asthma, adult-onsetasthma, cough-variant asthma, occupational asthma, steroid-resistantasthma, seasonal asthma, seasonal allergic rhinitis, perennial allergicrhinitis, and hypoxia.

In some embodiments, the LPAR1-mediated disease or condition includes anervous system disorder. In some embodiments, the nervous systemdisorder includes Alzheimer's Disease, cerebral edema, cerebralischemia, stroke, multiple sclerosis, neuropathies, Parkinson's Disease,a nervous condition found after blunt or surgical trauma (includingpost-surgical cognitive dysfunction and spinal cord or brain steminjury), as well as the neurological aspects of disorders such asdegenerative disk disease and sciatica.

In some embodiments, the LPAR1-mediated disease or condition includes acardiovascular disorder. In some embodiments, the cardiovasculardisorder includes arrhythmia (atrial or ventricular or both);atherosclerosis and its sequelae; angina; cardiac rhythm disturbances;myocardial ischemia; myocardial infarction; cardiac or vascularaneurysm; vasculitis; stroke; peripheral obstructive arteriopathy of alimb, an organ, or a tissue; reperfusion injury following ischemia ofthe brain, heart or other organ or tissue; endotoxic, surgical, ortraumatic shock; hypertension; valvular heart disease; heart failure;abnormal blood pressure; shock; vasoconstriction (including thatassociated with migraines); vascular abnormality, and a cardiovascularinsufficiency limited to a single organ or tissue.

In some embodiments, the LPAR1-mediated disease or condition includeslung fibrosis, kidney fibrosis, liver fibrosis, scarring, asthma,rhinitis, chronic obstructive pulmonary disease (COPD), pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, pain, proliferativedisorders and inflammatory conditions.

In some embodiments, the LPAR1-mediated disease or condition is a liverdisease. In some embodiments, the liver disease is hepatitis C, livercancer familial combined hyperlipidemia, non-alcoholic fatty liverdisease (NAFLD), progressive familial intrahepatic cholestasis, primarybiliary cirrhosis (PBC), or (PSC). In some embodiments, the liverdisease is PSC. In some embodiments the liver disease comprises portalhypertension. In some embodiments, liver cancer comprises hepatocellularcarcinoma (HCC), cholangiocarcinorna, angiosarcoma, or hemangiosarcoma.In some embodiments, liver cancer comprises HCC. In some embodiments,NAFLD comprises steatosis. In some embodiments, NAFLD comprises NASH. Insome embodiments, NAFLD or NASH comprises liver fibrosis. In someembodiments, NAFLD or NASH comprises liver cirrhosis. In someembodiments, the NAFLD or NASH comprises compensated liver cirrhosis. Insome embodiments, the NAFLD or NASH comprises decompensated liverfibrosis. In some embodiments, the NAFLD comprises HCC. In someembodiments, the liver disease is NASH.

In some embodiments, provided herein is a method of treating and/orpreventing NAFLD or NASH in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, or acomposition comprising a compound of (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or pharmaceutically acceptable saltthereof. In some embodiments, NAFLD or NASH comprise liver fibrosis. Insome embodiments, NAFLD or NASH comprise liver cirrhosis. In someembodiments, liver cirrhosis is compensated liver cirrhosis. In someembodiments, liver cirrhosis is decompensated liver cirrhosis. In someembodiments NAFLD or NASH comprise HCC.

In some embodiments, provided herein is a method of preventing a liverdisease or condition in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj), or pharmaceutically acceptable salt thereof, or acomposition comprising a compound of (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), or pharmaceutically acceptable saltthereof. In some embodiments, the liver disease or condition is liverfibrosis. In some embodiments, the liver disease or condition is livercirrhosis. In some embodiments, liver cirrhosis is compensated livercirrhosis. In some embodiments, liver cirrhosis is decompensated livercirrhosis. In some embodiments, the liver disease or condition is HCC.

In some embodiments, the present disclosure relates to the use ofcompounds according to Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj), or pharmaceutically acceptable salts thereof, in thepreparation of a medicament for the prophylaxis and/or treatment of anLPAR1-mediated disease or condition disclosed herein.

Dosage

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing an LPAR1 mediated disease or condition forwhich compounds of the present disclosure are indicated, generallysatisfactory results are obtained when the compounds of the presentdisclosure are administered at a daily dosage of from about 0.1milligram to about 300 milligram per kilogram of animal body weight. Insome embodiments, the compounds of the present disclosure are given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1 milligram to about 1000 milligrams, or from about 1milligram to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 0.1 milligrams toabout 200 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response. In some embodiments, the total dailydosage is from about 1 milligram to about 900 milligrams, about 1milligram to about 800 milligrams, about 1 milligram to about 700milligrams, about 1 milligram to about 600 milligrams, about 1 milligramto about 400 milligrams, about 1 milligram to about 300 milligrams,about 1 milligram to about 200 milligrams, about 1 milligram to about100 milligrams, about 1 milligram to about 50 milligrams, about 1milligram to about 20 milligram, or about 1 milligram to about 10milligrams.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds may be continued for a number of days; for example,commonly treatment would continue for at least 7 days, 14 days, or 28days, for one cycle of treatment. Treatment cycles are frequentlyalternated with resting periods of about 1 to 28 days, commonly about 7days or about 14 days, between cycles. The treatment cycles, in otherembodiments, may also be continuous.

In some embodiments, the methods provided herein comprise administeringto the subject an initial daily dose of about 1 to 800 mg of a compounddescribed herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, or once per week.

Combinations

In some embodiments, a compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), provided herein, or pharmaceuticallyacceptable salt thereof, is administered in combination with one or moreadditional therapeutic agents to treat or prevent a disease or conditiondisclosed herein. In some embodiments, the one or more additionaltherapeutic agents are one, two, three, or four additional therapeuticagents. In some embodiments, the one or more additional therapeuticagents are one additional therapeutic agent. In some embodiments, theone or more additional therapeutic agents are two additional therapeuticagents. In some embodiments, the one or more additional therapeuticagents are three additional therapeutic agents. In some embodiments, theone or more additional therapeutic agents are four additionaltherapeutic agents.

In some embodiments, the pharmaceutical compositions provided hereinhave a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj) provided herein, or pharmaceutically acceptable saltthereof, and one or more additional therapeutic agents. In someembodiments, the one or more additional therapeutic agents are one, two,three, or four additional therapeutic agents. In some embodiments, theone or more additional therapeutic agents are one additional therapeuticagent. In some embodiments, the one or more additional therapeuticagents are two additional therapeutic agents. In some embodiments, theone or more additional therapeutic agents are three additionaltherapeutic agents. In some embodiments, the one or more additionaltherapeutic agents are four additional therapeutic agents.

In some embodiments, the one or more additional therapeutic agents areselected from a(n) angiotensin converting enzyme (ACE) inhibitor,Adenosine A3 receptor agonist, Adiponectin receptor agonist, AKT proteinkinase inhibitor, AMP kinase activator, AMP-activated protein kinase(AMPK) activator, Amylin receptor agonist, Angiotensin II AT-1 receptorantagonist, Androgen receptor agonist, Apoptosis signal-regulatingkinase 1 (ASK1) inhibitor, ATP citrate lyase inhibitor, ApolipoproteinC₃ (APOC3) antagonist, Autophagy protein modulator, Autotaxininhibitors, Axl tyrosine kinase receptor inhibitor, Bax proteinstimulator, Bioactive lipid, Calcitonin agonist, Cannabinoid receptormodulator, Caspase inhibitor, Caspase-3 stimulator, Cathepsin inhibitor(e.g., cathepsin B inhibitor), Caveolin 1 inhibitor, CCR2 chemokineantagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, CD3antagonist, Chloride channel stimulator, cholesterol solubilizer, CNR1inhibitor, Cyclin D1 inhibitor, Cytochrome P450 7A1 inhibitor,Cytochrome P450 2E1 (CYP2E1) inhibitor, Diacylglycerol O acyltransferase1 inhibitor (DGAT1) inhibitor, Diacylglycerol O acyltransferase 1inhibitor (DGAT2) inhibitor, CXCR4 chemokine antagonist, Dipeptidylpeptidase IV inhibitor, Endosialin modulator, Endothelial nitric oxidesynthase stimulator, Eotaxin ligand inhibitor, Extracellular matrixprotein modulator, Farnesoid X receptor agonist, Fatty acid synthaseinhibitors, FGF1 receptor agonist, Fibroblast activation protein (FAP)inhibitor, Fibroblast growth factor receptor ligands (e.g., FGF-15,FGF-19, FGF-21), Fish oil, Galectin-3 inhibitor, Glucagon receptoragonist, Glucagon-like peptide 1 receptor agonist, Glucocorticoidreceptor antagonist, Glucose 6-phosphate 1-dehydrogenase inhibitor,Glutaminase inhibitor, Glutathione precursor, G-protein coupled bileacid receptor 1 agonist, G-protein coupled receptor 84 antagonist,Hedgehog (Hh) modulator, Hepatitis C virus NS3 protease inhibitor,Hepatocyte nuclear factor 4 alpha modulator (HNF4A), Hepatocyte growthfactor modulator, Histone deacetylase inhibitor, HMG CoA reductaseinhibitor, 11β-Hydroxysteroid dehydrogenase (11β-HSD 1) inhibitor,Hypoxia inducible factor-2 alpha inhibitor, IL-1β antagonist, IL-6receptor agonist, IL-10 agonist, IL-11 antagonist, IL-17 antagonist,Ileal sodium bile acid cotransporter inhibitor, Insulin sensitizer,Insulin ligand agonist, Insulin receptor agonist, integrin modulator,Integrin antagonist intereukin-1 receptor-associated kinase 4 (IRAK4)inhibitor, Jak2 tyrosine kinase inhibitor, Ketohexokinase (KHK)inhibitors, Klotho beta stimulator, leptin, leptin analog,5-Lipoxygenase inhibitor, Lipoprotein lipase inhibitor, Liver Xreceptor, LPL gene stimulator, Lysophosphatidate-1 receptor (LPAR-1)antagonist, Lysyl oxidase homolog 2 (LOXL2) inhibitor, LXR inverseagonist, Macrophage mannose receptor 1 modulator, Matrixmetalloproteinase (MMPs) inhibitor, MCH receptor-1 antagonist, MEKK-5protein kinase inhibitor, Membrane copper amine oxidase (VAP-1)inhibitor, Methionine aminopeptidase-2 inhibitor, Methyl CpG bindingprotein 2 modulator, MicroRNA-132 (miR-132) antagonist,MicroRNA-21(miR-21) inhibitor, Mitochondrial uncoupler, Mixed lineagekinase-3 inhibitor, Myelin basic protein stimulator, NACHT LRR PYDdomain protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin-1stimulator, NADPH oxidase inhibitor (NOX), Nicotinic acid receptor 1agonist, P2X7 purinoceptor modulator, P2Y13 purinoceptor stimulator, PDE3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor betamodulator, Peptidyl-prolyl cis-trans isomerase A inhibitor,Phenylalanine hydroxylase stimulator, Phospholipase C inhibitor, PPARalpha agonist, PPAR gamma agonist, PPAR delta agonist, PPAR gammamodulator, PPAR alpha/delta agonist, PPAR alpha/gamma/delta agonist,Protease-activated receptor-2 antagonist, Protein kinase modulator, Rhoassociated protein kinase 2 (ROCK2) inhibitor, Snitrosoglutathionereductase (GSNOR) enzyme inhibitor, Sodium glucose transporter-2 (SGLT2)inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor,STAT-3 modulator, Stearoyl CoA desaturase-1 inhibitor,Snitrosoglutathione reductase (GSNOR) enzyme inhibitor, Suppressor ofcytokine signalling-1 stimulator, Suppressor of cytokine signalling-3stimulator, Spleen tyorosine kinase (SYK) inhibitor, Transforming growthfactor β(TGF-β), TGF-β antagonist (e.g., TGF-β1 antagonist, TGF-β2antagonist, TGF-β3 antagonist, latent TGF β complex modulator), TGF-βreceptor antagonist, Transforming growth factor β activated Kinase 1(TAK1), Thyroid hormone receptor beta agonist, Toll-like receptor(TLR)-4 antagonist, Transglutaminase inhibitor, Tumor necrosis factoralpha (TNFα) ligand inhibitor, Tumor Progression Locus 2 (Tp12) kinaseinhibitor, Tyrosine kinase receptor modulator, GPCR modulator, nuclearhormone receptor modulator, WNT modulators, YAP/TAZ modulator, andZonulin inhibitor.

Non-limiting examples of the one or more additional therapeutic agentsinclude:

ACE inhibitors, such as enalapril;

Acetyl CoA carboxylase (ACC) inhibitors, such as NDI-010976(firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382 orPF-05221304;

Acetyl CoA carboxylase/Diacylglycerol O acyltransferase 2 inhibitors,such as PF-07055341;

Acetaldehyde dehydrogenase inhibitors, such as ADX-629;

Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101,CF-502, or CGS21680;

Adiponectin receptor agonists, such as ADP-355 or ADP-399;

Amylin/calcitonin receptor agonists, such as KBP-042 or KBP-089;

AMP activated protein kinase stimulators, such as PXL-770 or 0-304;

AMP kinase activators/ATP citrate lyase inhibitors, such as as bempedoicacid (ETC-1002, ESP-55016);

AMP activated protein kinase/Endothelial nitric oxidesynthase/NAD-dependent deacetylase sirtuin-1 stimulators, such asNS-0200 (leucine+metformin+sildenafil);

Androgen receptor agonists, such as LPCN-1144;

Angiotensin II AT-1 receptor antagonists, such as irbesartan;

Angiopoietin-related protein-3 inhibitors, such as IONIS-ANGPTL3-LRx;

Autotaxin inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165,PF-8380, AM-063, or BBT-877;

Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324,R-428);

Bax protein stimulators, such as CBL-514;

Bioactive lipids, such as DS-102;

Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab,GWP-42004, REV-200, or CRB-4001;

Caspase inhibitors, such as emricasan;

Pan cathepsin B inhibitors, such as VBY-376;

Pan cathepsin inhibitors, such as VBY-825;

CCR2/CCR5 chemokine antagonists, such as cenicriviroc, maraviroc,CCX-872, or WXSH-0213; CCR2 chemokine antagonists, such aspropagermanium;

CCR2 chemokine/Angiotensin II AT-1 receptor antagonists, such asDMX-200, or DMX-250;

CCR2/CCR5 chemokine antagonists and FXR agonists, such as LJC-242(tropifexor+cenivriviroc); CCR3 chemokine antagonists, such asbertilimumab;

Chloride channel stimulators, such as cobiprostone, or lubiprostone;

CD3 antagonists, such as NI-0401 (foralumab);

CXCR4 chemokine antagonists, such as AD-214;

Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

Diacylglycerol O acyltransferase 1 (DGAT1)/Cytochrome P450 2E1inhibitors (CYP2E1), such as SNP-610;

Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx,or PF-06865571;

Dipeptidyl peptidase IV inhibitors, such as linagliptin or evogliptin;

Eotaxin ligand inhibitors, such as bertilimumab or CM-101;

Extracellular matrix protein modulators, such as CNX-024;

Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256,EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674,LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480,MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228;

Farnesoid X receptor (FXR)/G-protein coupled bile acid receptor 1(TGR5)agonists, such as INT-767;

Fatty acid synthase inhibitors, such as TVB-2640;

FGF receptor agonists/Klotho beta stimulators, such as BFKB-8488A(RG-7992);

Fibroblast growth factor 19 (rhFGF19)/cytochrome P450 (CYP)₇A1inhibitors, such as NGM-282;

Fibroblast growth factor 21(FGF-21) ligand, such as BMS-986171,BIO89-100, B-1344, or BMS-986036;

Fibroblast growth factor 21(FGF-21)/glucagon like peptide 1 (GLP-1)agonists, such as YH-25723 (YH-25724; YH-22241) or AKR-001;

Fish oil compositions, such as icosapent ethyl (Vascepa®);

Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300), or GB1211(Gal-400);

Glucagon-like peptide 1 receptor (GLP1R) agonists, such as AC-3174,liraglutide, cotadutide (MEDI-0382), exenatide, SAR-425899, LY-3305677,HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, or semaglutide;

Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant);

Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

G-protein coupled bile acid receptor 1(TGR5) agonists, such as RDX-009or INT-777;

Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin,pitavastatin, pravastatin, rosuvastatin, or simvastatin;

Hypoxia inducible factor-2 alpha inhibitors, such as PT-2567;

IL-10 agonists, such as peg-ilodecakin;

Heal sodium bile acid cotransporter inhibitors, such as odevixibat(A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672,CJ-14199, or elobixibat (A-3309);

Insulin sensitizers, such as, KBP-042, MSDC-0602K, MSDC-5514, Px-102,RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101;

Insulin ligand/dslnsulin receptor agonists, such as ORMD-0801;

Integrin antagonists, such as IDL-2965;

IL-6 receptor agonists, such as KM-2702;

Ketohexokinase (KHK) inhibitors, such as PF-06835919;

beta Klotho (KLB)-FGF1c agonist, such as MK-3655 (NGM-313);

5-Lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102);

Lipoprotein lipase inhibitors, such as CAT-2003;

LPL gene stimulators, such as alipogene tiparvovec;

Liver X receptor (LXR) modulators, such as PX-L603, PX-L493, BMS-852927,T-0901317, GW-3965, or SR-9238;

Lysophosphatidate-1 receptor antagonists, such as BMT-053011, UD-009(CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198;

Lysyl oxidase homolog 2 inhibitors, such as simtuzumab or PXS-5382A(PXS-5338);

Macrophage mannose receptor 1 modulators, such as tilmanocept-Cy3(technetium Tc 99m tilmanocept);

Membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201;

MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015, orGS-444217, GST-HG-151;

MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

Methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839, orZN-1345;

Methyl CpG binding protein 2 modulators, such as mercaptamine;

Mitochondrial uncouplers, such as 2,4-dinitrophenol or HU6;

Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

Myelin basic protein stimulators, such as olesoxime;

NADPH oxidase 1/4 inhibitors, such as GKT-831 or APX-311;

Nicotinic acid receptor 1 agonists, such as ARI-3037M0;

Nitazoxinide;

NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such asKDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349);

Nuclear receptor modulators, such as DUR-928 (DV-928);

P2X7 purinoceptor modulators, such as SGM-1019;

P2Y13 purinoceptor stimulators, such as CER-209;

PDE 3/4 inhibitors, such as tipelukast (MN-001);

PDE 5 inhibitors, such as sildenafil or MSTM-102;

PDGF receptor beta modulators, such as BOT-191 or BOT-509;

Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431(CPI-432-32), NVP-018, or NV-556 (NVP-025);

Phenylalanine hydroxylase stimulators, such as HepaStem;

PPAR agonists (including PPAR alpha agonists, PPAR alpha/delta agonists,PPAR alpha/delta/gamma agonists, PPAR delta agonists), such aselafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer,pioglitazone, DRX-065, saroglitazar, or IVA-337; PPAR alpha agonists,such as aluminum clofibrate, bezafibrate, ciprofibrate, cholinefenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate,gemfibrozil, pemafibrate, ronifibrate, simfibrate, an omega-3 fatty acid(fish oil, e.g., icosapent ethyl (Vascepa®), or docosahexaenoic acid),pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939,aleglitazar, muraglitzar, or saroglitazar;

PPAR alpha/delta agonists such as elafibranor;

PPAR alpha/delta/gamma agonists such as lanifibranor;

PPAR delta agonists such as seladelpar;

Protease-activated receptor-2 antagonists, such as PZ-235;

Protein kinase modulators, such as CNX-014;

Rho associated protein kinase (ROCK) inhibitors, such as REDX-10178(REDX-10325) or KD-025;

Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1(SSAO/VAP-1) Inhibitors, such as PXS-4728A;

S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such asSL-891;

Sodium glucose transporter-2(SGLT2) inhibitors, such as ipragliflozin,remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, orsotagliflozin;

SREBP transcription factor inhibitors, such as CAT-2003 or MDV-4463;

Stearoyl CoA desaturase-1 inhibitors, such as aramchol;

Thyroid hormone receptor (THR) beta agonists, such as resmetriom(MGL-3196), MGL-3745, or VK-2809;

TLR-2/TLR-4 antagonists, such as VB-201 (CI-201);

TLR-4 antagonists, such as JKB-121;

Tyrosine kinase receptor modulators, such as CNX-025 or GFE-2137(repurposed nitazoxanide);

GPCR modulators, such as CNX-023;

Nuclear hormone receptor modulators, such as Px-102;

Xanthine oxidase/Urate anion exchanger 1 (URAT1) inhibitors, such asRLBN-1001, RLBN-1127; and

Zonulin Inhibitors, such as lorazotide acetate (INN-202).

In some embodiments, the one or more additional therapeutic agents areselected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogenetiparvovec, AMX-342, AN-3015, aramchol, ARI-3037MO, ASP-8232, AZD-2693,bertilimumab, Betaine anhydrous, BI-1467335, BMS-986036, BMS-986171,BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CBW-511, CER-209,CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone,colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazoneR-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305,elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin,F-351, fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621,GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201,hydrochlorothiazide, icosabutate (PRC-4016), icosapent ethyl ester,IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, Irbesarta,propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790,M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide,LJN-452 (tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100,MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301,MSDC-0602K, namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263),NGM-282, NGM-313, NGM-386, NGM-395, NP-160, norursodeoxycholic acid,NVP-022, 0-304, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505,PAT-048, PBI-4547, peg-ilodecakin, pioglitazone, pirfenidone, PRI-724,PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009,remogliflozin etabonate, RG-125 (AZD4076), RPI-500, saroglitazar,semaglutide, simtuzumab, solithromycin, sotagliflozin, statins(atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin,simvastatin), symbiotic, TCM-606F, TEV-45478, TQA-3526, tipelukast(MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid,VBY-376, VBY-825, VK-2809, vismodegib, volixibat potassium ethanolatehydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839,ZG-5216, ZSYM-008, and ZYSM-007.

In some embodients, the methods and pharmaceutical compositions providedherein include a therapeutically effective amount of an ApoptosisSignal-Regulating Kinase 1 (ASK1) inhibitor and a therapeuticallyeffective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist isa compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj), provided herein or pharmaceutically acceptable saltthereof.

In some embodiments of the methods and pharmaceutical compositionsdisclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).

ASK1 inhibitors can be synthesized and characterized using methods knownto those of skill in the art, such as those described in U.S.2007/0276050, U.S. 2011/0009410, and U.S. 2013/0197037.

In some embodiments, the methods and pharmaceutical compositionsprovided herein include a therapeutically effective amount of anAcetyl-CoA Carboxylase (ACC) inhibitor and a therapeutically effectiveamount of an LPAR1 antagonist, wherein the LPAR1 antagonist is acompound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or(IVa)-(IVj), provided herein or pharmaceutically acceptable saltthereof.

In some embodiments of the methods and pharmaceutical compositionsdisclosed herein, the ACC inhibitor is GS-0976 (firsocostat, FIR).

ACC inhibitors can be synthesized and characterized using methods knownto those of skill in the art, such as those described in U.S. Pat. Nos.9,453,026 and 10,183,951.

In some embodiments, the methods and compositions provided hereininclude a therapeutically effective amount of a PPAR agonist (e.g., PPARalpha agonist, PPAR alpha/delta agonist, PPARalpha/delta/gamma agonist,PPAR delta agonist) or fish oil, a therapeutically effective amount ofan Acetyl CoA Carboxylase (ACC) inhibitor, such as GS-0976 (firsocostat,FIR), and a therapeutically effective amount of an LPAR1 antagonist,wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (II),(IIa), (IIIa)-(IIIg), or (IVa)-(IVj), provided herein orpharmaceutically acceptable salt thereof. In some embodiments, the PPARagonist is a PPAR alpha agonist. In some embodiments, the PPAR alphaagonist is selected from aluminum clofibrate, bezafibrate, ciprofibrate,choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate,gemfibrozil, pemafibrate, ronifibrate, simfibrate, pirinixic acid,GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar,muraglitzar, and saroglitazar. In some embodiments, the PPAR agonist(e.g., PPAR alpha agonist) is a fibrate. In some embodiments, the PPARagonist (e.g., PPAR alpha agonist) is fenofibrate. In some embodiments,the PPAR agonist is a PPAR alpha/delta agonist (e.g., elafibranor). Insome embodiments, the PPAR agonist is a PPAR alpha/delta/gamma agonist(e.g., lanifibranor). In some embodiments, the PPAR agonist is a PPARdelta agonist (e.g., seladelpar). In some embodiments the fish oil is anomega-3 fatty acid or docosahexaenoic acid. In some embodiments, thefish oil is icosapent ethyl (e.g., Vascepa®).

In some embodiments, the methods and compositions provided hereininclude a therapeutically effective amount of a Farnesoid X Receptor(FXR) agonist and a therapeutically effective amount of an LPAR1antagonist, wherein the LPAR1 antagonist is a compound of Formula (I),(Ia), (II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj), provided herein orpharmaceutically acceptable salt thereof.

In some embodiments of the methods and pharmaceutical compositionsdisclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

In some embodiments of the methods and pharmaceutical compositionsdisclosed herein, the FXR agonist is a compound having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the methods and compositions provided hereininclude a therapeutically effective amount of a GLP-1 receptor agonistand a therapeutically effective amount of an LPAR1 antagonist, whereinthe LPAR1 antagonist is a compound of Formula (I), (Ia), (II), or (IIa)provided herein or a pharmaceutically acceptable salt thereof. In someembodiments, the GLP-1 receptor agonist is liraglutide or semaglutide.In some embodiments, the GLP-1 receptor agonist is semaglutide.

In some embodiments, the methods and compositions provided hereininclude a therapeutically effective amount of a TGFβ antagonist and atherapeutically effective amount of an LPAR1 antagonist, wherein theLPAR1 antagonist is a compound of Formula (I), (Ia), (II), (IIa),(IIIa)-(IIIg), or (IVa)-(IVj), provided herein or pharmaceuticallyacceptable salt thereof. In some embodiments, the TGFβ antagonist is aTGFβ1-specific antibody. TGFβ1-specific antibodies can be prepared andcharacterized using methods known to those of skill in the art, such asthose described in PCT International Application Publication No. WO2018/129329 and in U.S. Pat. No. 9,518,112. In some embodiments, theTGFβ antagonist binds to a TGFβ latency-associated peptide (LAP), e.g.,TGFβ1-LAP. TGFβ1-LAP-specific antibodies can be prepared andcharacterized using methods known to those of skill in the art, such asthose described in U.S. Pat. Nos. 8,198,412 or 10,017,567. In someembodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in acontext independent manner (e.g., independent of the presentation ofTGFβ in a specific tissue or organ). In some embodiments, the TGFβantagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner. Insome embodiments, the TGFβ antagonist blocks activation of latent TGFβ(e.g., latent TGFβ1) that is localized in extracellular matrix, e.g., inconnective tissue of the liver. In some embodiments, the TGFβ antagonistblocks activation of latent TGFβ (e.g., latent TGFβ1) that is localizedin the thymus, a lymph node, or in a tumor microenvironment (e.g., in apatient having liver cancer). In some embodiments, the TGFβ antagonistblocks activation of latent TGFβ (e.g., latent TGFβ1) by Latent TGFβBinding Protein (LTBP). In some embodiments, the TGFβ antagonist blocksactivation of latent TGFβ (e.g., latent TGFβ1) by Glycoprotein-ARepetitions Predominant protein (GARP), as described, e.g., in U.S. Pat.No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. Insome embodiments, the TGFβ antagonist is an anti-latency-associatedpeptide (LAP) antibody that specifically binds to a LAP-TGFβ1 complex.In some embodiments, the anti-LAP antibody specifically binds toLAP-TGFβ1 complexes in extracellular matrix (ECM), e.g., of connectivetissue in the liver. In some embodiments, the anti-LAP antibodyspecifically binds to LAP-TGFβ1 complexes on the surfaces of certainimmunosuppressive cell types, such as regulatory T cells (Tregs),tumor-associated macrophages, or myeloid-derived suppressor cells, e.g.,in a tumor microenvironment. In some embodiments, the anti-LAP antibodyis a TLS-01 antibody. In some embodiments, the anti-LAP antibodyspecifically binds to LAP-TGFβ1 complexes in any context. In someembodiments, the anti-LAP antibody is a TLS-02 antibody. In someembodiments, the TGFβ antagonist comprises a TGFβ receptor. In someembodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein.In some embodiments, the TGFβ antagonist is an antibody comprising aTGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that can beuseful in connection with the compositions and methods provided hereinhave been described, e.g., in PCT International Publication Nos. WO2019/113123 A1 and WO 2019/113464 A1.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that these examples are exemplary and notexhaustive. Many changes can be made in the specific embodiments whichare disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the disclosure.

Compounds disclosed herein can be prepared according to the proceduresof the following Schemes and Examples, using appropriate materials andare further exemplified by the following specific examples. Moreover, byutilizing the procedures described herein, in conjunction with ordinaryskills in the art, additional compounds of the present disclosureclaimed herein can be readily prepared. The examples further illustratedetails for the preparation of the compounds of the present disclosure.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. For synthesizing compounds whichare embodiments described in the present disclosure, inspection of thestructure of the compound to be synthesized will provide the identity ofeach substituent group. In some cases, the identity of the final productcan render apparent the identity of the necessary starting materials bya process of inspection, given the examples herein. Compounds can beisolated in the form of their pharmaceutically acceptable salts, such asthose described above. Compounds described herein are typically stableand isolatable at room temperature and pressure.

An illustration of the preparation of compounds disclosed herein isshown below. Unless otherwise indicated, variables have the same meaningas described above. The examples presented below are intended toillustrate particular embodiments of the disclosure. Suitable startingmaterials, building blocks and reagents employed in the synthesis asdescribed below are commercially available from AbovChem, AcrosOrganics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich,for example, or can be routinely prepared by procedures described in theliterature, for example in “March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure”, 5^(th) Edition; John Wiley & Sonsor T. Eicher, S. Hauptmann “The Chemistry of Heterocycles; Structures,Reactions, Synthesis and Application”, 2^(nd) edition, Wiley-VCH 2003;Fieser et al. “Fiesers' Reagents for organic Synthesis” John Wiley &Sons 2000.

General Schemes

Scheme A provides a general synthesis of bicyclic triazole carbamates(IX). Bicyclic halide VII can be readily prepared from electrophilicaromatic halogenation of the corresponding nitrogen-containing bicycle.Step one describes a general synthesis of bicyclic-containing triazolecarboxylic acids (VIII) via cross coupling reaction. Bicyclic halide(VII) can first be converted to the corresponding boronic ester such aspinacol boronate via Miyaura borylation, and then subjected to Suzukireaction conditions with bromo triazole carboxylic acid (III) to furnishthe desired bicyclic triazole carboxylic acid (VIII). Alternatively,bromo triazole carboxylic acid (III) can first be converted to anorgano-zinc species via lithium-halogen exchange and trapping with zincchloride. Next, Negishi cross coupling with bicyclic halide (VII)provides the desired bicyclic triazole carboxylic acid (VIII).

Step two describes a general synthesis of carbamate-containing bicyclictriazoles (IX). A bicyclic triazole carboxylic acid (VIII) undergoes aCurtius rearrangement when treated with diphenylphosphoryl azide (DPPA),or alternatively with 1-propanephosphonic anhydride (T3P) solution andazidotrimethylsilane. The intermediate isocyanate is then trapped withan alcohol (V) to provide the desired bicyclic triazole carbamate (IX).

Scheme B provides a general alternative synthesis of aryl, heteroaryl orbicyclic triazole carbamates (VI and IX). Step one describes a generalsynthesis of carbamate-containing bromo triazoles (X). A bromo triazolecarboxylic acid (III) undergoes a Curtius rearrangement when reactedwith diphenylphosphoryl azide (DPPA), or alternatively with1-propanephosphonic anhydride (T3P) solution and azidotrimethylsilane.The intermediate isocyanate is then trapped with an alcohol (V) toprovide the desired bromo triazole carbamate (X).

Step 2 describes a general synthesis for bicyclic triazole carbamate(IX) via cross coupling reaction. Bromo triazole carbamate (X) can firstbe converted to an organo-zinc species via lithium-halogen exchange andtrapping with zinc chloride. Next, Negishi cross coupling with bicyclichalide (VII), provides the desired bicyclic triazole carbamate (IX).Alternatively, bicyclic halide (VII) can first be converted to thecorresponding boronic ester such as pinacol boronate via Miyauraborylation, and then subjected to Suzuki reaction conditions with bromotriazole carbamate X to furnish the desired bicyclic triazole carbamate(IX).

Example 1: Preparation of4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1)

Step 1: 4,5-dibromo-2H-1,2,3-triazole

Bromine (2.8 mol) was added to a solution of 2H-1,2,3-triazole (1.4 mol)in water (600 mL) at 40° C. The resulting mixture was stirred for 2hours at 40° C. After cooling to room temperature, the precipitate wascollected by filtration. The solid was washed with water (2×300 mL) anddried under vacuum to give 4,5-dibromo-2H-1,2,3-triazole.

Step 2: 4,5-dibromo-1-methyl-1H-1,2,3-triazole

To a mixture of 4,5-dibromo-2H-1, 2, 3-triazole (704 mmol) and K₂CO₃(1.4 mol) in THF (1000 mL), iodomethane (1.0 mol) was added. The mixturewas stirred for 12 hours at room temperature. The mixture was filtered,and the filter cake was washed with ethyl acetate (2×500 mL), thefiltrate was concentrated under 40° C. to afford a crude product, whichwas purified by column chromatography to give4,5-dibromo-1-methyl-1H-1,2,3-triazole.

Step 3: 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde

To a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (168.0 mmol) inTHF (600 mL) was added isopropylmagnesium chloride (252.0 mmol) at −10°C. The mixture was stirred for 15 min, DMF (840 mmol) was added. After 1hour, the mixture was treated with 250 mL of saturated ammonium chlorideand extracted with DCM (2×350 mL). The combined organics were washedwith 250 mL of brine, dried over Na₂SO₄, filtered and concentrated togive 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde.

Step 4: 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

Oxone (651 mmol) was added to a solution of 4-bromo-1-methyl-1H-1, 2,3-triazole-5-carbaldehyde (536 mmol) in DMF (800 mL) and the resultingsuspension was stirred at room temperature overnight. The mixturereaction was diluted with H₂O (1000 mL), was adjusted to pH 3 with 1NHCl, and the aqueous phase was extracted with ethyl acetate (3×800 mL).The combined organics were washed with saturated Na₂CO₃ (2×500 mL), theaqueous phase was adjusted to pH 3 with 1N HCl. The precipitate wasisolated by filtration and dried under reduced pressure to provide4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1).

Example 2: Preparation of (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A)

To a suspension of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid(24.3 mmol) in toluene (80 mL) was added DPPA (24.5 mmol), triethylamine(24.5 mmol), and (R)-1-(2-chlorophenyl)ethan-1-ol (36.5 mmol). Themixture was heated at 80° C. for 3 hours. The reaction mixture wasfiltered, and the filtrate was concentrated in vacuo. The residue waspurified by silica chromatography to afford (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A).

Example 3: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B)

4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (95 mmol), 50%1-propanephosphonic anhydride solution (143 mmol) in DMF, andazidotrimethylsilane (143 mmol), were suspended in THF (350 mL) under anatmosphere of argon. Triethylamine (143 mmol) was added and theresulting solution was allowed to stir for 30 minutes.(R)-1-(2-chloropyridin-3-yl)ethan-1-ol (143 mmol) was added and themixture was heated at reflux, with a secondary bubbler attached to allowfor venting, for 12 hours. The reaction mixture was cooled to roomtemperature, and the THF was removed in vacuo. The resulting crudematerial was dissolved in 500 mL ethyl acetate and extracted three timeswith 300 mL water. The crude mixture was then dried over sodium sulfate,filtered and the filtrate was concentrated. The crude was purified bysilica gel column chromatography to provide(R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B).

Example 4: Preparation of (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C)

Following the procedure described in Example 3 for the synthesis of(R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B),using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (143 mmol) in place of(R)-1-(2-chloropyridin-3-yl)ethan-1-ol,(R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was obtained(Intermediate 2C).

Example 5: Preparation of1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (Intermediate 4)

4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, Intermediate 1(10.8 mmol) was dissolved in 98 mL of tetrahydrofuran and submerged in a−78° C. bath for 15 minutes. A 1 M solution of Lithiumbis(trimethylsilyl)amide in tetrahydrofuran (11.7 mmol) was dropwiseover 15 minutes. A 2.5 M solution of n-butylithium (19.6 mmol) inhexanes was added dropwise over minutes and allowed to stir for anadditional 1 hour. A 1.9 M solution of zinc chloride (24.5 mmol) in2-methyl tetrahydrofuran was added dropwise over 15 minutes. Thereaction mixture was warmed to ambient temperature by submerging in awater bath and allowed to stir for 30 minutes. The resulting mixture wassparged with argon gas for 10 minutes, and then6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2-one (9.78 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1 mmol) were added. The reaction was heated at 70°C. for 1 hour, and then cooled to ambient temperature. The reaction wasdiluted with 100 mL of a 2 M aqueous solution of sodium hydroxide and100 mL of diethyl ether. The aqueous layer was separated, and theorganic layer was extract with a 2M aqueous solution of sodium hydroxide(50 mL). The combined aqueous layer was washed with a 1:1 mixture ofethyl acetate and diethyl ether (100 mL×2). 25 mL of concentratedhydrochloric acid was dropwise over 15 minutes under vigorous stirringto adjust pH to 4. The mixture was filtered, and the filter cake waswashed with water (50 mL) and a 1:1 mixture of ethyl acetate and diethylether (50 mL×2). The precipitate was dried under reduced pressure toprovide1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (Intermediate 4).

Example 6: Alternative Preparation of1-methyl-4-(2-oxo-2,3-ddihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (Intermediate 4)

To a mixture of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid,Intermediate 1 (2.17 mmol) in tetrahydrofuran (14.5 mL) at −78° C. wasadded a 1 M solution of lithium bis(trimethylsilyl)amide (2.17 mmol) intetahydrofuran. After 10 minutes, a 2.5 M solution of n-butyllithium(4.35 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution ofzinc chloride (6.52 mmol) in 2-methyltetrahydrofuran was added, and thereaction was stirred at room temperature for 45 minutes. At this point6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2-one (1.45 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.145 mmol) were added to the reaction and the reactionmixture was heated to 70° C. for 1 hour. After completion of thereaction, the mixture was cooled and quenched with acetic acid. Themixture was concentrated under reduced pressure and purified by columnchromatography to provide1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (Intermediate 4).

Example 7: Preparation of 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol

2-Chloro-6-fluoronicotinaldehyde (2.51 mmol) dissolved in methyltetrahydrofuran (20 mL) was cooled in an ice/acetonitrile bath and thenmethylmagnesium bromide solution (3.0 M, 7.20 mmol) was added dropwise.The reaction mixture was quenched with addition of ethanol, and thendiluted with ethyl acetate and washed with 10% citric acid. The organiclayer was concentrated. The residue was purified by columnchromatography to give 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol.

Example 8: Preparation of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol

A solution of 2-fluoro-4-iodo-5-methylpyridine (4.22 mmol) in 20 mL THFwas cooled to 0° C. and treated with 1.6 M nBuLi in hexanes (5.06 mmol).After 15 min DMF (12.7 mmol) was added dropwise. The reaction wasstirred for 30 min, then warmed to room temperature and quenched withsat NH₄C₁. The mixture was extracted with EtOAc, dried with MgSO₄ andconcentrated to provide 2-fluoro-5-methylisonicotinaldehyde.2-fluoro-5-methylisonicotinaldehyde (5.5 mmol) was taken up in 25 mL THFand cooled to −15° C. in an ice-acetone bath. Treated with 3 M MeMgBr inTHF (11.2 mmol) and stirred for 20 minutes. Quenched with sat NH₄Cl andextracted with EtOAc, dried with MgSO₄, filtered and concentrated toprovide 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol (MS (m/z) 155.9[M+H]+).

Example 9: Preparation of 1-(2,5-difluoropyridin-4-yl)ethan-1-ol

Following the procedure described in Example 8 for the synthesis of1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using2,5-difluoroisonicotinaldehyde (11.9 mmol) in place of2-fluoro-5-methylisonicotinaldehyde,1-(2,5-difluoropyridin-4-yl)ethan-1-ol was obtained. (MS (m/z) 160.11[M+H]+)

Example 10: Preparation of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol

Following the procedure described in Example 8 for the synthesis of1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using5-bromo-2-fluoronicotinaldehyde (7.35 mmol) in place of2-fluoro-5-methylisonicotinaldehyde,1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol was obtained. (MS (m/z)220.01[M+H]+)

Example 11: Preparation of 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol

Following the procedure described in Example 8 for the synthesis of1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using5-bromo-2-chloronicotinaldehyde (10.6 mmol) in place of2-fluoro-5-methylisonicotinaldehyde,1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol was obtained. (MS (m/z)235.99[M+H]+)

Example 12: Preparation of 1-(2,5-difluoropyridin-4-yl)ethan-1-ol

Following the procedure described in Example 8 for the synthesis of1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using5-bromo-2-fluoronicotinaldehyde (7.4 mmol) in place of2-fluoro-5-methylisonicotinaldehyde,1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol. (MS (m/z) 220.01 [M+H]+)

Example 13: Preparation of Compounds 1 to 5

Compounds 1 to 5 were generally synthesized according Scheme A, Step 2.For example, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 1) was prepared as follows.

To a mixture of1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid, (Intermediate 4) (0.247 mmol), 1-propanephosphonic acid cyclicanhydride (50% in DMF, 0.371 mmol), and azidotrimethysilane (0.371 mmol)acid in THF (1.24 mL) was added triethylamine (0.494 mmol) dropwise.(1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.333 mmol) was added andthe reaction was heated at 70° C. for 1 hour. After completion of thereaction, the mixture was cooled and diluted with water. The mixture wasextracted with ethyl acetate (3×10 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by reverse-phase HPLC to provide(R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 1). (MS (m/z) 448.1 [M+H]+). ¹H NMR (400 MHz, Methanol-d₄) δ8.27 (s, 1H), 7.95 (dd, J=9.0, 3.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.32(s, 1H), 6.05 (q, J=6.5 Hz, 1H), 4.82 (s, 2H), 3.99 (s, 3H), 1.64 (s,3H).

Compounds 2-5 (Table 1) were similarly prepared according to Scheme A,Step 2 by reacting Intermediate 4 (Example 5 or 6) with the Reagentlisted in Table 1 in place of(1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol following the generalprocess described for Compound 1. Table 1: Compounds prepared accordingto Scheme A, Step 2.

TABLE 1 Compounds prepared according to Scheme A, Step 2. LCMS NameStructure Reagent m/z NMR Compound 2 1-(2,5-difluoropyridin- 4-yl)ethyl(1-methyl-4- (2-oxo-2,3-dihydro- 1H-pyrido[2,3-b][1,4]-oxazin-6-yl)-1H-1,2,3- triazol-5-yl)carbamate

432.1 1H NMR (400 MHz, Acetonitrile-d3) δ 8.77 (s, 1H), 8.26 (t, J = 1.9Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 5.3, 2.9 Hz, 1H), 7.32(d, J = 8.0 Hz, 1H), 5.99 (q, J = 6.7 Hz, 1H), 5.69 (dt, J = 9.5, 6.5Hz, 1H), 4.77 (s, 2H), 3.94 (s, 3H), 1.58- 1.55 (m, 3H). Compound 3(R)-1-(2,5-difluoro- pyridin-3-yl)ethyl (1- methyl-4-(2-oxo-2,3-dihydro-1H-pyrido- [2,3-b][1,4]oxazin-6- yl)-1H-1,2,3-triazol-5-yl)carbamate

432.0 1H NMR (400 MHz, Methanol-d4) δ 8.02 (d, 2H), 7.60 (d, J = 8.0 Hz,1H), 7.29 (d, J = 8.0 Hz, 1H), 5.95 (q, J = 6.7 Hz, 1H), 4.80 (s, 2H),3.96 (s, 3H), 1.62 (s, 3H). Compound 4 (R)-1-(5-chloro-2-fluoropyridin-3-yl)- ethyl (1-methyl-4-(2- oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]- oxazin-6-yl)-1H- 1,2,3-triazol-5-yl)- carbamate

448.1 1H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 2H), 7.60 (d, J = 8.0 Hz,1H), 7.29 (d, J = 7.6 Hz, 1H), 5.95 (q, J = 6.6 Hz, 1H), 4.79 (s, 2H),4.58 (s, 1H), 3.96 (s, 3H), 1.45 (d, J = 129.2 Hz, 3H). Compound 5(S)-2-fluoro-1-phenyl- ethyl (1-methyl-4-(2- oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]- oxazin-6-yl)-1H- 1,2,3-triazol-5-yl)- carbamate

431.1 1H NMR (400 MHz, Methanol-d4) δ 7.56 (d, J = 8.0 Hz, 1H),7.49-7.23 (m, 6H), 5.98 (dt, J = 16.9, 5.3 Hz, 1H), 4.79 (s, 2H),4.72-4.49 (m, 2H), 3.94 (s, 3H).

Example 14: Preparation of[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate(Compound 6)

Step 1:7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A mixture of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one (1.23 mmol),1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.123 mmol), Bis(pinacolato)diboron (1.84mmol), and potassium acetate (1.84 mmol) in 1,4-dioxane (12 mL) washeated to 100° C. for 4 hours. After completion of the reaction, themixture was cooled and diluted with water. The mixture was extractedwith ethyl acetate (3×10 mL). The combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography to provide7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one.

Step 2: [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate(Compound 6)

A mixture of7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(0.211 mmol), R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B)(0.222 mmol), and potassium carbonate (0.444 mmol) in 3:11,4-dioxane/water (3 mL) was heated to 80° C. for 30 minutes. Aftercompletion of the reaction, the mixture was cooled and diluted withwater. The mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified byreverse-phase HPLC to provide [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate(Compound 6). (MS (m/z) 445.1 [M+H]₊). ¹H NMR (400 MHz, Methanol-d₄) δ8.33 (s, 1H), 8.00 (s, 1H), 7.42 (d, J=7.6 Hz, 2H), 6.67 (d, J=11.2 Hz,1H), 6.04 (s, 1H), 3.95 (s, 3H), 2.95 (t, J=7.6 Hz, 2H), 2.60 (dd,J=8.5, 6.6 Hz, 2H), 1.60 (s, 3H).

Example 15: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 7)

Following the synthesis described in Example 14 for[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamatein step 1, 6-bromo-5-fluoro-3,4-dihydroquinolin-2(1H)-one (1.23 mmol)instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one,(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 7) was obtained. (MS (m/z) 445.1 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d₄) δ 8.36 (s, 1H), 8.03 (s, 1H), 7.44 (q, J=11.0, 7.9 Hz, 2H),6.78 (d, J=8.4 Hz, 1H), 6.09 (s, 1H), 3.98 (s, 3H), 2.99 (q, J=7.3 Hz,2H), 2.63 (t, J=7.8 Hz, 2H), 1.63 (s, 3H).

Example 16: Preparation of: (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 8)

Following the synthesis described in Example 14 for[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamatein step 1, using 7-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.31 mmol)instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one,(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 8) was obtained. (MS (m/z) 430.1 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d₄) δ 8.33 (s, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.04 (s, 1H), 7.59(d, J=1.9 Hz, 1H), 7.49 (s, 1H), 6.09 (q, J=6.6 Hz, 1H), 4.70 (s, 2H),3.94 (s, 3H), 1.63 (s, 3H).

Example 17: Preparation of (R)-1-(2-fluoropyridin-3-yl)ethyl(4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

Following the synthesis described in Example 14 for7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one,in step 1 using 6-bromo-4,4-dimethyl-1H-3,1-benzoxazin-2-one (1.17 mmol)instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one,4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-3,1-benzoxazin-2-onewas obtained.

Following the synthesis described in Example 14 for[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate,in step 2 using (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C) inplace of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B),(R)-1-(2-fluoropyridin-3-yl)ethyl(4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 9) was obtained. (MS (m/z) 441.1 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d₄) δ 8.18 (s, 1H), 8.05 (s, 1H), 7.59 (d, J=15.0 Hz, 2H), 7.37(s, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.02 (s, 1H), 3.94 (s, 3H), 1.67 (s,9H).

Example 18: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 10)

Following the synthesis described in Example 14 for7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one,in step 1 using 7-bromo-1,3,4,5-tetrahydro-1-benzazepin-2-one (0.833mmol) instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one,7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-1-benzazepin-2-onewas obtained.

Following the synthesis described in Example 14 for[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate,in step 2 using sodium carbonate (0.416 mmol) instead of potassiumcarbonate, (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 10) was obtained. (MS (m/z) 441.2 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d₄) δ 8.36 (s, 1H), 8.07 (s, 1H), 7.67-7.58 (m, 2H), 7.49 (s,1H), 7.09 (d, J=8.3 Hz, 1H), 6.13 (s, 1H), 3.96 (s, 3H), 2.82 (t, J=7.0Hz, 2H), 2.32 (d, J=6.7 Hz, 2H), 2.27 (q, J=7.0 Hz, 2H), 1.67 (s, 3H).

Example 19: Preparation of Compounds 11 to 20

Compounds 11 to 20 were generally synthesized according Scheme B, Step2. For example, (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 11) was prepared as follows.

A mixture of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(1.67 mmol), (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A)(0.556 mmol), and sodium carbonate (1.67 mmol) in 3:1 1,4-dioxane/water(7 mL) was heated to 100° C. for 1 hour. The mixture was cooled anddiluted with water. The mixture was extracted with ethyl acetate (3×10mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by reverse-phase HPLC to provide (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 11). (MS (m/z) 426.1 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d₄) δ7.61 (s, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.36 (d,J=33.0 Hz, 3H), 6.91 (d, J=8.2 Hz, 1H), 6.19 (s, 1H), 3.92 (s, 3H), 2.95(t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 1.61 (s, 3H).

Compounds 12-15 (Table 2) were similarly prepared according to Scheme B,Step 2 by reacting (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A)(Example 2) with the Reagent listed in Table 2 in place of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-onefollowing the general process described for Compound 11.

Compounds 16-18 (Table 2) were similarly prepared according to Scheme B,Step 2 by reacting R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B)(Example 3) with the Reagent listed in Table 2 in place of 6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-onefollowing the general process described for Compound 11.

TABLE 2 Compounds prepared according to Scheme B, Step 2. LCMS CompoundNo. Structure Reagent m/z 1H NMR Compound 11 (R)-1-(2-chloro-phenyl)ethyl (1- methyl-4-(2-oxo- 1,2,3,4-tetrahydro- quinolin-6-yl)-1H-1,2,3-triazol-5-yl)- carbamate

426.1 1H NMR (400 MHz, Methanol- d4) δ 7.61 (s, 1H), 7.54 (d, J = 1.7Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 33.0 Hz, 3H), 6.91 (d, J= 8.2 Hz, 1H), 6.19 (s, 1H), 3.92 (s, 3H), 2.95 (t, J = 7.6 Hz, 2H),2.58 (t, J = 7.6 Hz, 2H), 1.61 (s, 3H). Compound 12 (R)-1-(2-chloro-phenyl)ethyl (1- methyl-4-(2-oxo- 1,4-dihydro-2H- benzo[d][1,3]-oxazin-6-yl)-1H- 1,2,3-triazol-5-yl)- carbamate

428.1 1H NMR (400 MHz, Methanol- d4) δ 7.60 (d, J = 8.8 Hz, 2H), 7.52(d, J = 1.8 Hz, 1H), 7.49- 7.20 (m, 3H), 6.92 (d, J = 8.3 Hz, 1H), 6.19(d, J = 13.0 Hz, 1H), 5.31 (s, 2H), 3.92 (s, 3H), 1.59 (d, J = 6.6 Hz,3H). Compound 13 (R)-1-(2-chloro- phenyl)ethyl (1- methyl-4-(3-oxo-3,4-dihydro-2H- benzo[b][1,4]- oxazin-7-yl)-1H- 1,2,3-triazol-5-yl)-carbamate

428.1 1H NMR (400 MHz, Methanol- d4) δ 7.62 (s, 1H), 7.49-7.22 (m, 5H),6.93 (d, J = 8.6 Hz, 1H), 6.17 (s, 1H), 4.61 (s, 2H), 3.92 (d, J = 6.8Hz, 3H), 1.61 (s, 3H). Compound 14 (R)-1-(2-chloro- phenyl)ethyl (1-methyl-4-(2- oxoindolin-5-yl)- 1H-1,2,3-triazol- 5-yl)carbamate

412.1 1H NMR (400 MHz, Methanol- d4) δ 7.71-7.50 (m, 3H), 7.37 (d, J =31.5 Hz, 3H), 6.93 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 3.91 (s, 3H), 3.54(s, 2H), 1.70- 1.20 (m, 3H). Compound 15 (R)-1-(2-chloro- phenyl)ethyl(1- methyl-4-(2- oxo-1,2-dihydro- quinolin-6-yl)- 1H-1,2,3-triazol-5-yl)carbamate

424.1 1H NMR (400 MHz, Methanol- d4) δ 7.98 (d, J = 1.9 Hz, 1H),7.94-7.85 (m, 2H), 7.61 (s, 1H), 7.47-7.19 (m, 4H), 6.65 (d, J = 9.5 Hz,1H), 6.19 (s, 1H), 3.95 (s, 3H), 1.62 (s, 3H). Compound 16(R)-1-(2-chloro- pyridin-3-yl)ethyl (1-methyl-4-(2- oxo-1,4-dihydro-2H-benzo[d][1,3]- oxazin-6-yl)-1H- 1,2,3-triazol-5-yl)- carbamate

429.1 1H NMR (400 MHz, Methanol- d4) δ 8.35 (s, 1H), 8.04 (s, 1H), 7.59(d, J = 8.3 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.48 (s, 1H), 6.93 (d, J= 8.2 Hz, 1H), 6.09 (s, 1H), 5.33 (s, 2H), 3.93 (s, 3H), 1.65 (s, 3H).Compound 17 (R)-1-(2-chloro- pyridin-3-yl)ethyl (1-methyl-4-(2-oxo-1,2,3,4-tetra- hydroquinolin-6- yl)-1H-1,2,3- triazol-5-yl)-carbamate

427.1 1H NMR (400 MHz, Methanol- d4) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.55(s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.21 (s, 1H), 6.91 (d, J = 8.3 Hz,1H), 6.11 (s, 1H), 3.92 (s, 3H), 2.97 (t, J = 7.6 Hz, 2H), 2.66-2.51 (m,2H), 1.65 (s, 3H). Compound 18 (R)-1-(2-chloro- pyridin-3-yl)ethyl(1-methyl-4-(3- oxo-3,4-dihydro- 2H-benzo[b][1,4]- oxazin-7-yl)-1H-1,2,3-triazol-5-yl)- carbamate

429.1 1H NMR (400 MHz, Methanol- d4) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.48(s, 1H), 7.37-7.27 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.10 (s, 1H), 4.62(s, 2H), 3.92 (s, 3H), 1.65 (s, 3H).

Example 20: Preparation of (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(4-methyl-2-oxo-1,2,3,4-tetrahydropuinoxalin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 19)

A mixture of 6-bromo-4-methyl-1,3-dihydroquinoxalin-2-one (0.556 mmol),1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride,dichloromethane complex (0.0278 mmol), Bis(pinacolato)diboron (0.834mmol), and potassium acetate (0.834 mmol) in 1,4-dioxane (3 mL) washeated to 100° C. for 1 hour. At this point, the reaction was cooled toroom temperature, and (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A)(0.278 mmol), potassium carbonate (0.834 mmol), and water (1 mL) wereadded to the reaction. The reaction was purged with nitrogen and heatedto 100° C. for 1 hour. After completion of the reaction, the mixture wascooled and diluted with water. The mixture was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse-phase HPLC to provide (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(4-methyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 19). (MS (m/z) 441.1 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d₄) δ7.61 (s, 1H), 7.48-7.24 (m, 3H), 7.12 (s, 2H), 6.85 (d, J=8.1 Hz, 1H),6.22 (q, J=6.3, 5.9 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 2.82 (s, 3H),1.59 (d, J=6.6 Hz, 3H).

Example 21: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydropuinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 20)

Step 1:3-methyl-5-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)triazole-4-carboxylicacid

A mixture of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(0.583 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid(Intermediate 1) (0.485 mmol), and potassium carbonate (1.46 mmol) in3:1 1,4-dioxane/water (6 mL) was heated to 100° C. for 6 hours. Aftercompletion of the reaction, the mixture was cooled and quenched with 1MHCl (5 mL), resulting in precipitate formation. The precipitated solidswere filtered to provide3-methyl-5-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)triazole-4-carboxylicacid.

Step 2: [(1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethyl]N-[3-methyl-5-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)triazol-4-yl]carbamate(Compound 20)

To a mixture of3-methyl-5-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)triazole-4-carboxylicacid (0.294 mmol), 1-propanephosphonic acid cyclic anhydride (50% inDMF, 0.441 mmol), and azidotrimethysilane (0.441 mmol) acid in THF (1.5mL) was added triethylamine (0.588 mmol) dropwise.(1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.396 mmol) was added andthe flask was heated at 70° C. for 1 hour. After completion of thereaction, the mixture was cooled and diluted with water. The mixture wasextracted with ethyl acetate (3×10 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by reverse-phase HPLC to provide(R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 20) (MS (m/z) 445.1 [M+H]⁺). ¹H NMR (400 MHz, DMSO-d₆) δ 10.18(s, 1H), 9.96 (s, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.59-7.36 (m, 2H),6.87 (d, J=8.2 Hz, 1H), 5.91 (s, 1H), 3.84 (s, 3H), 2.87 (t, J=7.6 Hz,2H), 2.45 (d, J=7.7 Hz, 2H), 1.61 (s, 3H).

Example 22: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 21)

Step 1: 6-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one

To a suspension of 3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (5.61mmol) in acetonitrile (56 mL) was added N-bromosuccinimide (6.17 mmol)followed by Trifluoroacetic acid (1.12 mmol). The reaction was thenheated at 70° C. for 8 hours. After completion of the reaction, themixture was diluted with water. The mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to yield6-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one.

Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 21)

To a mixture of of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B)(0.42 mmol) in THF (4.2 mL) at −78° C. was added a 1 M solution oflithium bis(trimethylsilyl)amide in THF (0.46 mmol). After 10 minutes, a2.5 M solution of n-butyllithium (0.83 mmol) in Hexanes was added. After45 minutes, a 1.9 M solution of zinc chloride (1.3 mmol) in 2-MeTHF wasadded, and the reaction was stirred at room temperature for 45 minutes.At this point 6-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one(0.39 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (0.042 mmol) were added to the reaction and thereaction mixture was heated to 70° C. for 1 hour. After completion ofthe reaction, the mixture was cooled and quenched with saturated aqueousammonium chloride. The mixture was diluted with ethyl acetate andorganics were separated. The aqueous layer was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse-phase HPLC to provide(R)-1-(2-chloropyridin-3-yl)ethyl(4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 21) (MS (m/z) 458.1 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d₄) δ8.38-7.93 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.52-7.35 (m, 1H), 7.35-7.24(m, 1H), 6.08 (q, J=6.4 Hz, 1H), 3.95 (s, 3H), 1.74-1.43 (m, 9H).

Example 23: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 22)

Following the synthesis described in Example 19 for(R)-1-(2-chloropyridin-3-yl)ethyl(4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 21), using 3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (0.609mmol) instead of 3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one in step1, (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 22) was obtained (MS (m/z) 444.1 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d4) δ 8.42-7.92 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.42 (s, 1H),7.31 (s, 1H), 6.08 (q, J=6.6 Hz, 1H), 4.94-4.90 (m, 1H), 4.58 (s, 3H),3.95 (s, 3H), 1.58 (d, J=6.9 Hz, 3H).

Example 24: Preparation of (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 23)

To a mixture of (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A)(0.139 mmol) in THF (1.4 mL) at −78° C. was added a 2.5 M solution ofn-butyllithium (0.417 mmol) in Hexanes was added. After 30 minutes, a1.9 M solution of zinc chloride (0.417 mmol) in 2-MeTHF was added, andthe reaction was stirred at room temperature for 45 minutes. At thispoint 6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (0.139 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (0.0139 mmol) were added to the reaction and thereaction mixture was heated to 70° C. for 1 hour. After completion ofthe reaction, the mixture was cooled and quenched with saturated aqueousammonium chloride. The mixture was diluted with ethyl acetate andorganics were separated. The aqueous layer was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse-phase HPLC to provide (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 23) (MS (m/z) 429.0 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d4) δ7.64-7.50 (m, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.34-7.17 (m, 3H), 6.16 (q,J=6.6 Hz, 1H), 4.82 (s, 2H), 3.94 (s, 3H), 1.56 (s, 3H).

Example 25: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 24)

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B)(2.77 mmol) in THF (28 mL) at −78° C. was added a 1 M solution oflithium bis(trimethylsilyl)amide (3.05 mmol) in THF. After 10 minutes, a2.5 M solution of n-butyllithium (6.93 mmol) in Hexanes was added. After45 minutes, a 1.9 M solution of zinc chloride (9.71 mmol) in 2-MeTHF wasadded, and the reaction was stirred at room temperature for 45 minutes.At this point 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2-one (2.77 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (0.277 mmol) were added to the reaction and thereaction mixture was heated to 70° C. for 1 hour. After completion ofthe reaction, the mixture was cooled and quenched with saturated aqueousammonium chloride. The mixture was diluted with ethyl acetate andorganics were separated. The aqueous layer was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse-phase HPLC to provide(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 24) (MS (m/z) 430.0 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d₄) δ8.30 (s, 1H), 8.12 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.31(s, 1H), 6.11 (dd, J=22.0, 6.6 Hz, 1H), 4.90 (s, 2H), 3.95 (s, 3H), 1.63(d, J=6.6 Hz, 3H).

Example 26: Preparation of[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[3-methyl-5-(2-oxo-1,4-dihydropyrido[3,2-d][1,3]oxazin-6-yl)triazol-4-yl]carbamate(Compound 25)

Following the synthesis described in Example 25 for(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate,using 6-bromo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-2-one (0.277 mmol)instead of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, and(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (0.0277 mmol) instead of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex, [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[3-methyl-5-(2-oxo-1,4-dihydropyrido[3,2-d][1,3]oxazin-6-yl)triazol-4-yl]carbamate(Compound 25) was obtained. (MS (m/z) 430.0 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d₄) δ 8.31 (d, J=19.5 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=8.4 Hz,1H), 7.43 (s, 1H), 7.30 (s, 1H), 6.11 (s, 1H), 5.33 (s, 2H), 3.99 (s,3H), 1.63 (d, J=17.1 Hz, 3H).

Example 27: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 26)

Following the synthesis described in Example 25 for(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate,using 6-bromo-3-ethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.555 mmol)instead of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one,(R)-1-(2-chloropyridin-3-yl)ethyl(4-(3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 26) was obtained. (MS (m/z) 458.0 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d₄) δ 8.30 (s, 1H), 8.11 (s, 1H), 7.60 (dd, J=8.0, 3.2 Hz, 1H),7.41 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.08 (d, J=6.5 Hz, 1H), 4.79-4.71(m, 1H), 3.96 (s, 3H), 2.09-1.82 (m, 2H), 1.62 (s, 3H), 1.08 (q, J=7.1Hz, 3H).

Example 28: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(I-methyl-4-(2-oxo-3-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 27)

Following the synthesis described in Example 25 for(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate,using 6-bromo-3-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.555mmol) instead of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one,(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-3-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 27) was obtained. (MS (m/z) 506.0 [M+H]⁺). ¹H NMR (400 MHz,DMSO-d6) δ 11.19 (d, J=4.6 Hz, 1H), 9.82 (s, 1H), 8.30 (d, J=26.8 Hz,1H), 7.96 (s, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.48-7.31 (m, 6H), 7.27 (s,1H), 6.01 (d, J=13.3 Hz, 1H), 5.86 (s, 1H), 3.86 (s, 3H), 1.35 (d,J=83.8 Hz, 3H).

Example 29: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(7-fluoro-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 28)

Following the synthesis described in Example 25 for(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate,using 6-bromo-7-fluoro-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.555mmol) instead of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, and(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.0555 mmol)instead of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(7-fluoro-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 28) was obtained. (MS (m/z) 448.0 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d4) δ 8.32 (s, 1H), 8.06 (s, 1H), 7.45 (d, J=5.7 Hz, 1H), 7.12(s, 1H), 6.09-6.00 (m, 1H), 4.82 (s, 2H), 3.97 (s, 3H), 1.63 (d, J=6.8Hz, 3H).

Example 30: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 29)

Following the synthesis described in Example 14 for[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamatein step 1, 6-bromo-8-fluoro-3,4-dihydroquinolin-2(1H)-one (0.82 mmol)instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one,(R)-1-(2-chloropyridin-3-yl)ethyl(4-(8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate(Compound 29) was obtained. (MS (m/z) 445.2 [M+H]⁺). ¹H NMR (400 MHz,Methanol-d4) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 7.38 (d, J=5.5Hz, 1H), 7.35 (d, J=1.7 Hz, 1H), 6.11 (s, 1H), 3.93 (s, 3H), 3.02 (t,J=7.6 Hz, 2H), 2.69-2.51 (m, 2H), 1.75-1.22 (m, 3H).

Example 31: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(I-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 30)

Step 1: Methyl2-[(6-bromo-3-nitro-2-pyridyl)oxy]-3,3,3-trifluoro-propanoate

To a suspension of 2,6-dibromo-3-nitro-pyridine (3.55 mmol) and methyl3,3,3-trifluoro-2-hydroxy-propanoate (3.90 mmol) in THF (6 mL) was addedsodium hydride (4.26 mmol) at 0° C. The reaction was stirred at roomtemperature. After completion of the reaction, the mixture was dilutedwith water. The reaction mixture was extracted with ethyl acetate (3×10mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure to provide methyl2-[(6-bromo-3-nitro-2-pyridyl)oxy]-3,3,3-trifluoro-propanoate. Thismaterial was carried on without further purification.

Step 2: 6-bromo-3-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2-one

To a suspension of methyl2-[(6-bromo-3-nitro-2-pyridyl)oxy]-3,3,3-trifluoro-propanoate (3.55mmol) in acetic acid (10 mL) was added iron powder (24.8 mmol) andheated to 80° C. for 30 minutes. After completion of the reaction, thereaction mixture was cooled to room temperature and filtered throughcelite. The filter cake was washed with ethyl acetate, and the combinedfiltrate was concentrated. The residue was purified by columnchromatography to provide6-bromo-3-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2-one.

Step 3:1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid

4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, Intermediate 1(2.43 mmol) was dissolved in 24 mL of tetrahydrofuran and submerged in a−78° C. bath for 15 minutes. A 1 M solution of Lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.67 mmol) was dropwiseover 15 minutes. A 2.5 M solution of n-butylithium (4.85 mmol) inhexanes was added dropwise over 20 minutes and allowed to stir for anadditional 1 hour. A 1.9 M solution of zinc chloride (7.52 mmol) in2-methyl tetrahydrofuran was added dropwise over 15 minutes. Thereaction mixture was warmed to ambient temperature by submerging in awater bath and allowed to stir for 30 minutes. The resulting mixture wassparged with argon gas for 10 minutes, and then6-bromo-3-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2-one (1.70mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (0.24 mmol) were added. The reaction washeated at 70° C. for 1 hour, and then cooled to ambient temperature. Thereaction was diluted with 20 mL of a 2 M aqueous solution of sodiumhydroxide and 20 mL of diethyl ether. The aqueous layer was separated,and the organic layer was extracted with a 2M aqueous solution of sodiumhydroxide (20 mL). The combined aqueous layer was washed with a 1:1mixture of ethyl acetate and diethyl ether (20 mL×2). 5 mL ofconcentrated hydrochloric acid was dropwise over 15 minutes undervigorous stirring to adjust pH to 4. The mixture was filtered, and thefilter cake was washed with water (10 mL) and a 1:1 mixture of ethylacetate and diethyl ether (10 mL×2). The precipitate was dried underreduced pressure to provide1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid.

Step 4: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate

To a mixture of1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (0.208 mmol), 1-propanephosphonic acid cyclic anhydride (50% inDMF, 0.312 mmol), and azidotrimethysilane (0.312 mmol) acid in THF (1.05mL) was added triethylamine (0.417 mmol) dropwise.(1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.309 mmol) was added andthe reaction was heated at 70° C. for 1 hour. After completion of thereaction, the mixture was cooled and concentrated under reducedpressure. The residue was purified by reverse-phase HPLC to provide(R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 30). (MS (m/z) 516.0 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ8.27 (s, 1H), 7.92 (s, 1H), 7.73 (dd, J=8.0, 3.1 Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 6.05 (d, J=6.9 Hz, 1H), 5.64-5.44 (m, 1H), 3.99 (s, 3H), 1.64(s, 3H).

Example 32: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 31)

Step 1: 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a suspension of 3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (6.09mmol) in acetonitrile (60 mL) was added N-bromosuccinimide (6.70 mmol)followed by Trifluoroacetic acid (1.22 mmol). The reaction was thenheated at 70° C. for 8 hours. After completion of the reaction, themixture was diluted with water. The mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to yield6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.

Step 2:1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid

4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, Intermediate 1(2.43 mmol) was dissolved in 24 mL of tetrahydrofuran and submerged in a−78° C. bath for 15 minutes. A 1 M solution of Lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.67 mmol) was dropwiseover 15 minutes. A 2.5 M solution of n-butylithium (4.85 mmol) inhexanes was added dropwise over 20 minutes and allowed to stir for anadditional 1 hour. A 1.9 M solution of zinc chloride (7.52 mmol) in2-methyl tetrahydrofuran was added dropwise over 15 minutes. Thereaction mixture was warmed to ambient temperature by submerging in awater bath and allowed to stir for 30 minutes. The resulting mixture wassparged with argon gas for 10 minutes, and6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.70 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.24 mmol) were added. The reaction was heated at70° C. for 1 hour, and then cooled to ambient temperature. The reactionwas diluted with 20 mL of a 2 M aqueous solution of sodium hydroxide and20 mL of diethyl ether. The aqueous layer was separated, and the organiclayer was extracted with a 2M aqueous solution of sodium hydroxide (20mL). The combined aqueous layer was washed with a 1:1 mixture of ethylacetate and diethyl ether (20 mL×2). 5 mL of concentrated hydrochloricacid was dropwise over 15 minutes under vigorous stirring to adjust pHto 4. The mixture was filtered, and the filter cake was washed withwater (10 mL) and a 1:1 mixture of ethyl acetate and diethyl ether (10mL×2). The precipitate was dried under reduced pressure to provide1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid.

Step 3: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate

To a mixture of1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (0.211 mmol), 1-propanephosphonic acid cyclic anhydride (50% inDMF, 0.312 mmol), and azidotrimethysilane (0.316 mmol) acid in THF (1.05mL) was added triethylamine (0.422 mmol) dropwise.(1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.313 mmol) was added andthe reaction was heated at 70° C. for 1 hour. After completion of thereaction, the mixture was cooled and concentrated under reducedpressure. The residue was purified by reverse-phase HPLC to provide(R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 31). (MS (m/z) 462.0 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d4) δ8.24 (s, 1H), 7.90 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 6.04(q, J=6.6 Hz, 1H), 4.95-4.87 (m, 1H), 3.97 (s, 3H), 1.61 (s, 3H), 1.56(d, J=6.9 Hz, 3H).

Example 33: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 32)

Step 1: 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a suspension of 3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (6.09mmol) in acetonitrile (60 mL) was added N-bromosuccinimide (6.70 mmol)followed by Trifluoroacetic acid (1.22 mmol). The reaction was thenheated at 70° C. for 8 hours. After completion of the reaction, themixture was diluted with water. The mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to yield6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.

Step 2: tert-butyl1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylate

Tert-butyl 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylate (1.53 mmol)was dissolved in 5.5 mL of tetrahydrofuran and submerged in a −78° C.bath for 15 minutes. A 1 M solution of Lithium bis(trimethylsilyl)amidein tetrahydrofuran (1.68 mmol) was dropwise over 15 minutes. A 2.5 Msolution of n-butylithium (3.05 mmol) in hexanes was added dropwise over20 minutes and allowed to stir for an additional 1 hour. A 1.9 Msolution of zinc chloride (4.73 mmol) in 2-methyl tetrahydrofuran wasadded dropwise over 15 minutes. The reaction mixture was warmed toambient temperature by submerging in a water bath and allowed to stirfor 30 minutes. The resulting mixture was sparged with argon gas for 10minutes, and 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(1.53 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.15 mmol) were added. The reaction was heated at70° C. for 1 hour. After completion of the reaction, the mixture wascooled to room temperature and quenched with ammonium chloride. Themixture was extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography toyield tert-butyl1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylate.

Step 3:1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid

To a solution of tert-butyl1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylate(0.20 mmol) was added trifluoroacetic acid (0.98 mmol). Reaction wascomplete after 3 hours and concentrated under reduced pressure to yield1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid. The material was carried forward without further purification.

Step 4: (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate

To a mixture of1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylicacid (0.211 mmol), 1-propanephosphonic acid cyclic anhydride (50% inDMF, 0.313 mmol), and azidotrimethysilane (0.316 mmol) acid in THF (1.05mL) was added triethylamine (0.422 mmol) dropwise.(1R)-1-(2,5-difluoro-3-pyridyl)ethanol (0.313 mmol) was added and thereaction was heated at 70° C. for 1 hour. After completion of thereaction, the mixture was cooled and concentrated under reducedpressure. The residue was purified by reverse-phase HPLC to provide(R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate(Compound 32). (MS (m/z) 446.0 [M+H]⁺). ¹H NMR (400 MHz, Methanol-d4) δ7.96 (d, J=44.1 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H),6.05-5.86 (m, 1H), 4.94-4.89 (m, 1H), 3.96 (s, 3H), 1.73-1.42 (m, 6H).

Example 34: Calcium Assay

In vitro LPAR1 activity was measured in an intracellular calciummobilization assay.

CHO-K1 EDG2 cells (DiscoverX cat #93-0644C₂) expressing human LPAR1 (NM001401.3) were seeded in a total volume of 25 μL of Dulbecco'sModification of Eagle's Medium (DMEM) with 10% Fetal Bovine Serum, lxPenStrepGlutamine, 300 ug/ml Hygromycin, and 800 ug/ml G418 into384-well tissue culture plate (Grenier #781091) at 15,000 cells/well andincubated at 37° C. overnight. Prior to testing, 25 tL Calcium LoadingDye Component A (FLIPR Calcium 6 Assay Kit Molecular Device # R8190) and2.5 mM Probenecid (Invitrogen # P36400, prepared fresh) in Hank'sBalanced Salt Solution (Corning #21-023-CV), 20 mM HEPES (Corning#25-060-CI), 0.1% Bovine Serum Albumin (Sigma-Aldrich # A7906-500G) wasadd to the cells for 60 minutes at 37° C.

Agonist dose curves of LPA 18:2 (Avanti Polar Lipids cat #857138, 0.5 nMto 10 μM) were recorded to determine the LPA 18:2 EC₈₀ for subsequentantagonist assays. For agonist dose curves, cells were removed from theincubator 2 hours after dye loading and transferred to the FLIPR Tetrainstrument (Molecular Devices, San Jose, Calif.). Calcium mobilizationwas monitored for 5 min and 10 μL 6×LPA in HBSS/20 mM Hepes/0.1% bovineserum albumin (BSA) was added to the cells 5 seconds into the assay.

To determine the LPAR1 antagonist activity of test compounds, cells werepre-incubated with test compound at a dose range of 0.5 nM to 10 μM,followed by LPA at EC₈₀ concentration (100 nM). After dye loading, cellswere removed from the incubator and 0.3 μL of 200× antagonist was added.Cells were incubated for 60 minutes at 37° C. Antagonist activity wasmeasured on a FLIPR Tetra. Calcium mobilization was monitored for 3.5minutes and 10 μL 6× EC₈₀ LPA in HBSS, 20 mM HEPES, and 0.1% BSA wasadded to the cells 5 seconds into the assay. Signal amplitude (Maximumminus minimum) values were plotted against log₁₀ of antagonistconcentration using Dose Response Tool (Gilead Sciences Inc.) todetermine EC₅₀.

To assess the antagonistic potential of exemplified compounds EC₅₀values were determined for Compounds 1 to 32 in the LPAR1 calciummobilization assay. Results are shown in Table 3 (LPAR1 EC₅₀). Thecompound numbers correspond to the compound numbers in Examples 1 to 33.

TABLE 3 LPAR1 Compound (EC₅₀; [nM]) Compound 1 85 Compound 2 1,984Compound 3 66 Compound 4 118 Compound 5 100 Compound 6 115 Compound 71,234 Compound 8 765 Compound 9 4,606 Compound 10 N/A Compound 11 46Compound 12 218 Compound 13 38 Compound 14 4,157 Compound 15 565Compound 16 525 Compound 17 390 Compound 18 265 Compound 19 265 Compound20 118 Compound 21 2,280 Compound 22 86 Compound 23 N/A Compound 24 123Compound 25 140 Compound 26 3,783 Compound 27 135 Compound 28 660Compound 29 5 Compound 30 <5 Compound 31 <5 Compound 32 3,783

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

Thus, it should be understood that although the present disclosure hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification, improvement and variation of the disclosuresembodied therein herein disclosed may be resorted to by those skilled inthe art, and that such modifications, improvements and variations areconsidered to be within the scope of this disclosure. The materials,methods, and examples provided here are representative of preferredembodiments, are exemplary, and are not intended as limitations on thescope of the disclosure.

The disclosure has been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of the disclosure. This includes thegeneric description of the disclosure with a proviso or negativelimitation removing any subject matter from the genus, regardless ofwhether or not the excised material is specifically recited herein.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

1. A compound of Formula (I):

or pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen orC₁₋₆ alkyl optionally substituted with 1 to 3 substituents, which can bethe same or different, each independently selected from halogen, cyano,C₁₋₄ alkoxy, and C₃₋₁₀ cycloalkyl; or R¹ is C₃₋₆ cycloalkyl optionallysubstituted with 1 to 3 substituents, which can be the same ordifferent, each independently selected from halogen, cyano, C₁₋₄ alkoxy,and C₁₋₆ alkyl; each R², which can be the same or different, isindependently selected from hydrogen, halogen, cyano, oxo, C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6to 10 membered aryl, 5 to 10 membered heteroaryl having 1 to 4heteroatoms independently selected from nitrogen, oxygen, or sulfur,—N(R^(2A1))(R^(2A2)), O—R^(2A1), —S—R^(2A1), —C(O)N(R^(2A1))(R^(2A2)),—NR^(2A1)C(O)R^(2A2), —NR^(2A1)C(O)N(R^(2A2))(R^(2A3)), —S(O)₀₋₂R^(2A1),—S(O)₂N(R^(2A1))(R^(2A2)), and —NR^(2AA)S(O)₂R^(2A2), wherein eachR^(2A1), R^(2A2), and R^(2A3) is independently hydrogen or C₁₋₆ alkyl,wherein each R² alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl isoptionally substituted with 1 to 4 R^(2B), which can be the same ordifferent, wherein each R^(2B) is independently C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, halogen, or cyano; each R³, which can be the same or different,is independently selected from deuterium, halogen, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, or C₁₋₄ alkoxy, wherein each C₁₋₆ alkyl and C₃₋₁₀cycloalkyl, is optionally substituted with 1 to 3 halogens; R⁴ is C₁₋₆alkyl optionally substituted with 1 to 3 substituents, which can be thesame or different, each independently selected from halogen, cyano, C₁₋₄alkoxy, —C(O)N(R^(4A1)), and —N(R^(4A1))(R^(4A2)) wherein each R^(4A1)and R^(4A2) is independently H, C₁₋₆ alkyl, or C₃₋₁₀ cycloalkyl; or R⁴is C₃₋₆ cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cycloalkyl or heterocyclyl are optionally substituted with 1to 3 substituents, which can be the same or different, eachindependently selected from halogen, cyano, C₁₋₄ alkyl and C₁₋₄ alkoxy;m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; each ofX¹, X², and X³ is independently selected from CH and N; each U isindependently —CH═, —CH₂—, —N═, —NH—, or —O—; each Y¹ and Y² isindependently hydrogen, deuterium, or C₁₋₆ alkyl optionally substitutedwith 1 to 3 substituents, which can be the same or different, eachindependently selected from deuterium, halogen, cyano, C₂₋₃ alkynyl,C₁₋₄ alkoxy, and —C(O)NH—(C₁₋₄H₃₋₉); and Z is C₁₋₈ alkyl, C₁₋₆ alkoxy,C₃₋₆ cycloalkyl, C₆₋₁₂ aryl, 3 to 12 membered heterocyclyl having 1 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur, or5 to 12 membered heteroaryl having 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy,cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionallysubstituted with 1 to 3 substituents, which can be the same ordifferent, each independently selected from halogen, cyano, C₁₋₄ alkyl,C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl, wherein the C₁₋₄ alkyl is optionallysubstituted with 1 to 3 substituents, which can be the same ordifferent, each selected from C₁₋₄ alkoxy and halogen; or Y¹ and Ztogether with the carbon to which they are attached form C₃₋₆cycloalkyl, C₆₋₁₂ aryl, 3 to 12 membered heterocyclyl having 1 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur, or5 to 12 membered heteroaryl having 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl,aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1to 3 substituents, which can be the same or different, eachindependently selected from cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₆₋₁₀ aryland halogen, wherein the C₁₋₄ alkyl is optionally substituted with 1 to3 substituents, which can be the same or different, each independentlyselected from C₁₋₄ alkoxy and halogen, and wherein the C₆₋₁₀ aryl isoptionally substituted with 1 to 3 substituents, which can be the sameor different, each independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,and halogen, and Y² is hydrogen or deuterium.
 2. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (Ia):

3.-10. (canceled)
 11. The compound or pharmaceutically acceptable saltthereof of claim 1, wherein the compound is of Formula (IIIa):

wherein: m is 0, 1, or 2; and o is 0, 1, 2, or
 3. 12. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (IIIb):

wherein: m is 0, 1, 2, 3, or 4; and o is 0, 1, 2, or
 3. 13. The compoundor pharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (IIIc):

wherein: m is 0, 1 or 2; and o is 0, 1, 2, or
 3. 14. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (IIId):

wherein: m is 0, 1, or 2; and o is 0, 1, 2, or
 3. 15. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (IIIe)

wherein: m is 0, 1, or 2; and o is 0, 1, 2, or
 3. 16. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (IIIf):

wherein: m is 0, 1, 2, or 3; and o is 0, 1, 2, or
 3. 17. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound is of Formula (IIIg):

wherein: m is 0, 1, 2, 3, or 4; and o is 0, 1, 2, or
 3. 18. The compoundor pharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVa):

wherein m is 0, 1, or 2; and is 0, 1, 2, or
 3. 19. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVb):

wherein m is 0, 1, 2, 3, or 4; and o is 0, 1, 2, or
 3. 20. The compoundor pharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVc):

wherein m is 0, 1, or 2; and o is 0, 1, 2, or
 3. 21. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVd):

wherein m is 0, 1, or 2; and is 0, 1, 2, or
 3. 22. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVe):

wherein m is 0, 1, or 2; and o is 0, 1, or
 2. 23. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVf):

wherein m is 0, 1, or 2; and o is 0, 1, 2, or
 3. 24. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVg)

wherein m is 0, 1, or 2; and o is 0, 1, or
 2. 25. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVh):

wherein m is 0, 1, or 2; and o is 0, 1, or
 2. 26. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVi):

wherein m is 0, 1, or 2; o is 0, 1, 2, or
 3. 27. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein thecompound of Formula (IVj):

wherein m is 0, 1, 2, 3, or 4; and o is 0, 1, 2, or
 3. 28-36. (canceled)37. The compound or pharmaceutically acceptable salt thereof of claim 1,wherein each R², which can be the same or different, is independently—CH₃, —CF₃, —C₂H₅, phenyl, or —F. 38.-41. (canceled)
 42. The compound orpharmaceutically acceptable salt thereof of claim 1, wherein R³ is —F.43.-45. (canceled)
 46. The compound or pharmaceutically acceptable saltthereof of claim 1, wherein Y₁ is —CH₃ or —CH₂F. 47.-49. (canceled) 50.The compound or pharmaceutically acceptable salt thereof of claim 1,wherein Z is

51.-52. (canceled)
 53. The compound or pharmaceutically acceptable saltthereof of claim 1, wherein Z is

54.-61. (canceled)
 62. A pharmaceutical composition comprising atherapeutically effective amount of a compound, or pharmaceuticallyacceptable salt thereof, of claim 1, and a pharmaceutically acceptableexcipient.
 63. (canceled)
 64. A method of treating, stabilizing, orlessening the severity or progression of an LPAR1 mediated disease orcondition comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof. 65.-98. (canceled)